Liposome Technology blog

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Targeted drug delivery strategies to treat lung metastasis.

Expert Opin Drug Deliv. 2009 Oct;6(10):1003-16

Authors: Bar J, Herbst RS, Onn A

BACKGROUND: Most cancer patients die of metastatic disease, and in a high proportion of cases, from lung metastasis. Methods to target therapy to metastatic disease in general and specifically to lung metastasis are required. OBJECTIVE: To describe the current and potential tools for the treatment of lung metastasis. METHODS: Literature search tools were used with no predefined limitations to encompass the main tumor targeting methods. Methods in standard clinical use, in clinical trials and in preclinical development are reviewed. Data about treatment of lung metastasis and solid tumors are emphasized. RESULTS: Physically targeting therapies to lung metastasis is feasible by aerosol-carried agents, magnetic targeting and intravascular devices. Biological targeting includes methods such as polymers and liposomes, which are based on the principle of enhanced permeability and retention of large molecules in tumor vascular field. Ligand-targeted treatments depend on cancer-specific antibodies or receptors. Few of these methods are in clinical trials or in standard clinical use. However, promising techniques are in advanced preclinical or early clinical studies. The authors believe that targeted treatments will be one the major anticancer tools in the near future.

PMID: 19663628 [PubMed - indexed for MEDLINE]

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Drug targeting through pilosebaceous route.

Curr Drug Targets. 2009 Oct;10(10):950-67

Authors: Chourasia R, Jain SK

Local skin targeting is of interest for the pharmaceutical and the cosmetic industry. A topically applied substance has basically three possibilities to penetrate into the skin: transcellular, intercellular, and follicular. The transfollicular path has been largely ignored because hair follicles constitute only 0.1% of the total skin. The hair follicle is a skin appendage with a complex structure containing many cell types that produce highly specialised proteins. The hair follicle is in a continuous cycle: anagen is the hair growth phase, catagen the involution phase and telogen is the resting phase. Nonetheless, the hair follicle has great potential for skin treatment, owing to its deep extension into the dermis and thus provides much deeper penetration and absorption of compounds beneath the skin than seen with the transdermal route. In the case of skin diseases and of cosmetic products, delivery to sweat glands or to the pilosebaceous unit is essential for the effectiveness of the drug. Increased accumulation in the pilosebaceous unit could treat alopecia, acne and skin cancer more efficiently and improve the effect of cosmetic substances and nutrients. Therefore, we review herein various drug delivery systems, including liposomes, niosomes, microspheres, nanoparticles, nanoemulsions, lipid nanocarriers, gene therapy and discuss the results of recent researches. We also review the drugs which have been investigated for pilosebaceous delivery.

PMID: 19663765 [PubMed - indexed for MEDLINE]

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Liposomal delivery of doxorubicin to hepatocytes in vivo by targeting heparan sulfate.

Int J Pharm. 2009 Dec 1;382(1-2):222-33

Authors: Longmuir KJ, Haynes SM, Baratta JL, Kasabwalla N, Robertson RT

Previous work demonstrated that liposomes, containing an amino acid sequence that binds to hepatic heparan sulfate glycosaminoglycan, show effective targeting to liver hepatocytes. These liposomes were tested to determine whether they can deliver doxorubicin selectively to liver and hepatocytes in vivo. Fluid-phase liposomes contained a lipid-anchored 19-amino acid glycosaminoglycan targeting peptide. Liposomes were loaded with doxorubicin and were non-leaky in the presence of serum. After intravenous administration to mice, organs were harvested and the doxorubicin content extracted and measured by fluorescence intensity and by fluorescence microscopy. The liposomal doxorubicin was recovered almost entirely from liver, with only trace amounts detectable in heart, lung, and kidney. Fluorescence microscopy demonstrated doxorubicin preferentially in hepatocytes, also in non-parenchymal cells of the liver, but not in cells of heart, lung or kidney. The doxorubicin was localized within liver cell nuclei within 5 min after intravenous injection. These studies demonstrated that liposomal doxorubicin can be effectively delivered to hepatocytes by targeting the heparan sulfate glycosaminoglycan of liver tissue. With the composition described here, the doxorubicin was rapidly released from the liposomes without the need for an externally supplied stimulus.

PMID: 19664697 [PubMed - indexed for MEDLINE]

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The use of pH-triggered leaky heterogeneities on rigid lipid bilayers to improve intracellular trafficking and therapeutic potential of targeted liposomal immunochemotherapy.

Biomaterials. 2009 Oct;30(30):6055-64

Authors: Karve S, Alaouie A, Zhou Y, Rotolo J, Sofou S

During endocytosis, pH-triggered release of encapsulated therapeutics from delivery carriers may accelerate their intracellular trafficking increasing therapeutic efficacy. To improve the therapeutic potential of targeted immunochemotherapy using anti-HER2/neu liposomal doxorubicin, we exploit the formation of leaky heterogeneities on rigid lipid bilayers to extensively release doxorubicin during endocytosis. We have previously demonstrated that pH-dependent formation of phase-separated lipid heterogeneities on the plane of a bilayer membrane increases the permeability of bilayers when they are composed of lipid pairs with rigid non-matching acyl chain lengths. This was suggested to be due to defective packing among lipids residing at the interfaces of lipid domains. Here we design nanometer-size antiHER2/neu-labeled PEGylated vesicles composed of lipid pairs with longer non-matching acyl chain lengths (n=18 and 21). These vesicles exhibit superior killing efficacy of cancer cells compared to established liposome formulations, and their killing efficacy is similar to the effect of combined free doxorubicin and free antiHER2/neu antibody. Other transport-related properties such as liposome blood circulation times, and specific binding and internalization by cancer cells are unaffected. These results demonstrate the potential of vesicles with pH-triggered leaky heterogeneities to increase the therapeutic potential of targeted immunochemotherapy.

PMID: 19665223 [PubMed - indexed for MEDLINE]

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The antimicrobial activity of liposomal lauric acids against Propionibacterium acnes.

Biomaterials. 2009 Oct;30(30):6035-40

Authors: Yang D, Pornpattananangkul D, Nakatsuji T, Chan M, Carson D, Huang CM, Zhang L

This study evaluated the antimicrobial activity of lauric acid (LA) and its liposomal derivatives against Propionibacterium acnes (P. acnes), the bacterium that promotes inflammatory acne. First, the antimicrobial study of three free fatty acids (lauric acid, palmitic acid and oleic acid) demonstrated that LA gives the strongest bactericidal activity against P. acnes. However, a setback of using LA as a potential treatment for inflammatory acne is its poor water solubility. Then the LA was incorporated into a liposome formulation to aid its delivery to P. acnes. It was demonstrated that the antimicrobial activity of LA was not only well maintained in its liposomal derivatives but also enhanced at low LA concentration. In addition, the antimicrobial activity of LA-loaded liposomes (LipoLA) mainly depended on the LA loading concentration per single liposomes. Further study found that the LipoLA could fuse with the membranes of P. acnes and release the carried LA directly into the bacterial membranes, thereby killing the bacteria effectively. Since LA is a natural compound that is the main acid in coconut oil and also resides in human breast milk and liposomes have been successfully and widely applied as a drug delivery vehicle in the clinic, the LipoLA developed in this work holds great potential of becoming an innate, safe and effective therapeutic medication for acne vulgaris and other P. acnes associated diseases.

PMID: 19665786 [PubMed - indexed for MEDLINE]

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Polyethylene glycol-complexed cationic liposome for enhanced cellular uptake and anticancer activity.

Int J Pharm. 2009 Dec 1;382(1-2):254-61

Authors: Jung SH, Jung SH, Seong H, Cho SH, Jeong KS, Shin BC

Liposomes as one of the efficient drug carriers have some shortcomings such as their relatively short blood circulation time, fast clearance from human body by reticuloendothelial system (RES) and limited intracellular uptake to target cells. In this study, polyethylene glycol (PEG)-complexed cationic liposomes (PCL) were prepared by ionic complex of cationically charged liposomes with carboxylated polyethylene glycol (mPEG-COOH). The cationic liposomes had approximately 98.6+/-1.0 nm of mean particle diameter and 45.5+/-1.1 mV of zeta potential value. While, the PCL had 110.1+/-1.2 nm of mean particle diameter and 18.4+/-0.8 mV of zeta potential value as a result of the ionic complex of mPEG-COOH with cationic liposomes. Loading efficiency of model drug, doxorubicin, into cationic liposomes or PCL was about 96.0+/-0.7%. Results of intracellular uptake evaluated by flow cytometry and fluorescence microscopy studies showed higher intracellular uptake of PCL than that of Doxil. In addition, in vitro cytotoxicity of PCL was comparable to cationic liposomes. In pharmacokinetic study in rats, PCL showed slightly lower plasma level of DOX than that of Doxil. In vivo antitumor activity of DOX-loaded PCL was comparable to that of Doxil against human SKOV-3 ovarian adenocarcinoma xenograft rat model. Consequently, the PCL, of which surface was complexed with PEG by ionic complex may be applicable as drug delivery carriers for increasing therapeutic efficacy of anticancer drugs.

PMID: 19666094 [PubMed - indexed for MEDLINE]

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Drug ratio-dependent antitumor activity of irinotecan and cisplatin combinations in vitro and in vivo.

Mol Cancer Ther. 2009 Aug;8(8):2266-75

Authors: Tardi PG, Dos Santos N, Harasym TO, Johnstone SA, Zisman N, Tsang AW, Bermudes DG, Mayer LD

Irinotecan and cisplatin are two established anticancer drugs, which together constitute an effective combination for treating small-cell lung cancer. We investigated whether the efficacy of this combination could be improved by controlling drug ratios following in vivo administration. Irinotecan and cisplatin combinations were evaluated systematically for drug ratio-dependent synergy in vitro using a panel of 20 tumor cell lines. In vitro screening informatics on drug ratio-dependent cytotoxicity identified a consistently antagonistic region between irinotecan/cisplatin molar ratios of 1:2 to 4:1, which was bordered by two synergistic regions. Liposomal co-formulations of these two agents were developed that exhibited plasma drug half-lives of approximately 6 hours and maintained a fixed drug ratio for more than 24 hours. Drug ratio-dependent antitumor activity was shown in vivo for these liposome formulations, and irinotecan/cisplatin ratios between 5:1 and 10:1 were identified as therapeutically optimal. The relationship between irinotecan/cisplatin ratio and in vivo efficacy was consistent with in vitro drug ratio dependency results. Superior antitumor activity was observed for the liposome-encapsulated 7:1 molar ratio of irinotecan/cisplatin (designated CPX-571) compared with the free-drug cocktail in all models tested. Further efficacy studies in a range of human tumor xenografts, including an irinotecan-resistant model, showed that both liposomal agents contributed to the overall efficacy in a manner consistent with in vivo synergy. These results show the ability of drug delivery technology to enhance the therapeutic activity of irinotecan/cisplatin combination treatment by maintaining synergistic ratios in vivo. CPX-571, a fixed-ratio formulation of irinotecan and cisplatin, is a promising candidate for clinical development.

PMID: 19671743 [PubMed - indexed for MEDLINE]

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Liquid crystalline phases of dendritic lipid-DNA self-assemblies: lamellar, hexagonal, and DNA bundles.

J Phys Chem B. 2009 Mar 26;113(12):3694-703

Authors: Zidovska A, Evans HM, Ewert KK, Quispe J, Carragher B, Potter CS, Safinya CR

The prospects of gene therapy have generated unprecedented interest in the properties and structures of complexes of nucleic acids (NAs) with cationic liposomes (CLs), which are used as nonviral NA carriers in worldwide clinical trials. An improved understanding of the mechanisms of action of CL-NA complexes is required to enable their widespread therapeutic use. In prior studies of CL-mediated DNA delivery, membrane charge density (sigma(M)) was identified as a key parameter for transfection efficiency (TE) of lamellar (L(alpha)(C)) CL-DNA complexes. The TE of CL-DNA complexes containing cationic lipids with headgroup valencies from 1+ to 5+ follows a universal bell-shaped curve as a function of sigma(M). As we report here, the TE of CL-DNA complexes containing new multivalent lipids with dendritic headgroups (DLs) strongly deviates from this curve at high sigma(M). We have investigated four DLs, MVLG2 (4+), MVLG3 (8+), MVLBisG1 (8+), and MVLBisG2 (16+), in mixtures with neutral 1,2-dioleoyl-sn-glycerophosphatidyl-choline (DOPC). To understand the TE behavior, we have performed X-ray diffraction (XRD), optical microscopy, and cryo-TEM studies of the DL/DOPC mixtures and their DNA complexes. XRD reveals a complex phase behavior of DL-DNA complexes which strongly depends on the headgroup charge. MVLG2(4+)/DOPC-DNA complexes exhibit the lamellar phase at all molar fractions of DL, Phi(DL). In stark contrast, MVLBisG2(16+)/ DOPC-DNA complexes remain lamellar only for Phi(DL) < or = 0.2. In a narrow regime around Phi(DL) = 0.25, the hexagonal phase H(I)(C), consisting of a hexagonal lattice of cylindrical lipid micelles and a DNA honeycomb lattice, is formed. At Phi(DL) > 0.3, XRD suggests formation of a distorted H(I)(C) phase. For Phi(DL) > or = 0.5 under high salt conditions, this phase coexists with a bundle phase of DNA condensed by the depletion-attraction effect of DL micelles. The transitions at high sigma(M) from the lamellar phase to the new hexagonal phases of DL-DNA complexes coincide with the deviation from the universal TE behavior of lamellar complexes. The observed high TE, which is independent of sigma(M), strongly suggests a novel mechanism of action for these DL-DNA complex phases.

PMID: 19673065 [PubMed - indexed for MEDLINE]

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Role of block copolymer nanoconstructs in cancer therapy.

Crit Rev Ther Drug Carrier Syst. 2009;26(2):157-205

Authors: Upadhyay KK, Agrawal HG, Upadhyay C, Schatz C, Le Meins JF, Misra A, Lecommandoux S

Drug, gene, and protein delivery is a very challenging and exciting area in nanobiotechnology where block copolymers are increasingly considered especially as carriers for pharmacotherapy of various cancers. Cancer chemotherapy is particularly challenging because of nonselective distribution of drugs, associated severe toxicity, multidrug resistance, and chronic treatments influencing the quality-adjusted life of patients. These limitations lead to incomplete cure and render many drugs ineffective in treating cancers. Liposomes are currently more advanced in clinical trials and industrial developments but they lack stability and pose difficulties in functionalizing liposomes. More recently, various types of polymer-based nanoconstructs have been designed and synthesized, and are being investigated for the cancer chemotherapy applications. This review discusses the most significant and recent developments on specific self-assembled block copolymers as a carrier system such as micelles and vesicles, which can be successfully used to enhance the solubility of hydrophobic drugs, helpful in targeting selective sites in the body, delivering active molecules in a control manner, and reducing the side effects in the treatment of cancer.

PMID: 19673690 [PubMed - indexed for MEDLINE]

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Archaeosomes made of Halorubrum tebenquichense total polar lipids: a new source of adjuvancy.

BMC Biotechnol. 2009;9:71

Authors: Gonzalez RO, Higa LH, Cutrullis RA, Bilen M, Morelli I, Roncaglia DI, Corral RS, Morilla MJ, Petray PB, Romero EL

BACKGROUND: Archaeosomes (ARC), vesicles prepared from total polar lipids (TPL) extracted from selected genera and species from the Archaea domain, elicit both antibody and cell-mediated immunity to the entrapped antigen, as well as efficient cross priming of exogenous antigens, evoking a profound memory response. Screening for unexplored Archaea genus as new sources of adjuvancy, here we report the presence of two new Halorubrum tebenquichense strains isolated from grey crystals (GC) and black mood (BM) strata from a littoral Argentinean Patagonia salt flat. Cytotoxicity, intracellular transit and immune response induced by two subcutaneous (sc) administrations (days 0 and 21) with BSA entrapped in ARC made of TPL either form BM (ARC-BM) and from GC (ARC-GC) at 2% w/w (BSA/lipids), to C3H/HeN mice (25 microg BSA, 1.3 mg of archaeal lipids per mouse) and boosted on day 180 with 25 microg of bare BSA, were determined. RESULTS: DNA G+C content (59.5 and 61.7% mol BM and GC, respectively), 16S rDNA sequentiation, DNA-DNA hybridization, arbitrarily primed fingerprint assay and biochemical data confirmed that BM and GC isolates were two non-previously described strains of H. tebenquichense. Both multilamellar ARC mean size were 564 +/- 22 nm, with -50 mV zeta-potential, and were not cytotoxic on Vero cells up to 1 mg/ml and up to 0.1 mg/ml of lipids on J-774 macrophages (XTT method). ARC inner aqueous content remained inside the phago-lysosomal system of J-774 cells beyond the first incubation hour at 37 degrees C, as revealed by pyranine loaded in ARC. Upon subcutaneous immunization of C3H/HeN mice, BSA entrapped in ARC-BM or ARC-GC elicited a strong and sustained primary antibody response, as well as improved specific humoral immunity after boosting with the bare antigen. Both IgG1 and IgG2a enhanced antibody titers could be demonstrated in long-term (200 days) recall suggesting induction of a mixed Th1/Th2 response. CONCLUSION: We herein report the finding of new H. tebenquichense non alkaliphilic strains in Argentinean Patagonia together with the adjuvant properties of ARC after sc administration in mice. Our results indicate that archaeosomes prepared with TPL from these two strains could be successfully used as vaccine delivery vehicles.

PMID: 19678953 [PubMed - indexed for MEDLINE]

Related Articles

Real-time electrochemical monitoring of drug release from therapeutic nanoparticles.

J Control Release. 2009 Nov 16;140(1):69-73

Authors: Mora L, Chumbimuni-Torres KY, Clawson C, Hernandez L, Zhang L, Wang J

An electrochemical protocol for real-time monitoring of drug release kinetics from therapeutic nanoparticles (NPs) is described. The method is illustrated for repetitive square-wave voltammetric measurements of the reduction of doxorubicin released from liposomes at a glassy-carbon electrode. Such operation couples high sensitivity down to 20 nM doxorubicin with high speed and stability. It can thus monitor in real time the drug release from NP carriers, including continuous measurements in diluted serum. Such direct and continuous monitoring of the drug release kinetics from therapeutic NPs holds great promise for designing new drug delivery NPs with optimal drug release properties. These NPs can potentially be used to deliver many novel compounds such as marine-life derived drugs and hydrophobic drugs with limited water solubility that are usually difficult to be characterized by traditional analytical tools.

PMID: 19679152 [PubMed - indexed for MEDLINE]

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Liposomes as an ocular delivery system of fluconazole: in-vitro studies.

Acta Ophthalmol. 2009 Aug 14;

Authors: Habib FS, Fouad EA, Abdel-Rhaman MS, Fathalla D

. Purpose: To study the clinical effect of topical controlled-release ophthalmic fluconazole liposomal formulation and to compare its effect with fluconazole solution in a reproducible model of Candida keratitis in rabbits. Methods: Forty adult rabbits were included in this study. Right eyes were inoculated with freshly prepared Caindida albicans strain no. 4925 and showed signs of infected keratitis. The rabbits were divided randomly into two groups: in the first group (18 rabbits) the right eyes received fluconazole solution, while in the second group (22 rabbits) the right eyes received fluconazole-loaded liposomes. The rabbits' eyes were examined daily over a 21-day period and results were recorded. Results: Rabbits infected with C. albicans responded better and showed more improvement in terms of size of ulcer and hypopyon using fluconazole-loaded liposomal formulae than using fluconazole solution. In the first group (solution), nine rabbits' cornea showed complete healing (50%) at the end of third week while in group 2 (liposome), 19 rabbits' cornea showed complete healing (86.4%) at equal duration. These results were statistically significant. Conclusion: Therapy with topical liposomal fluconazole (2 mg/ml) was successful in eliminating experimental C. albicans infection of the rabbit cornea and was superior to fluconazole solution.

PMID: 19681761 [PubMed - as supplied by publisher]

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Elastic liposomes for topical and transdermal drug delivery.

Curr Drug Deliv. 2009 Jul;6(3):217-26

Authors: Benson HA

Elastic vesicles have been developed and evaluated as novel topical and transdermal delivery systems. They are similar to conventional liposomes but with the incorporation of an edge activator in the lipid bilayer structure to provide elasticity. Elastic vesicles are applied non-occluded to the skin and have been shown to permeate through the stratum corneum lipid lamellar regions as a result of the hydration or osmotic force in the skin. They have been investigated as drug carriers for a range of small molecules, peptides, proteins and vaccines, both in vitro and in vivo. Following topical application, structural changes in the stratum corneum have been identified and intact elastic vesicles visualised within the stratum corneum lipid lamellar regions, but no intact vesicles have been identified in the deeper viable tissues. Their method of transporting their drug payload into and through the skin has been investigated but remains an area of contention. This review provides an overview of the development of elastic vesicles for delivery into and via the skin.

PMID: 19604135 [PubMed - indexed for MEDLINE]

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Mucoadhesive liposomes for intranasal immunization with an avian influenza virus vaccine in chickens.

Biomaterials. 2009 Oct;30(29):5862-8

Authors: Chiou CJ, Tseng LP, Deng MC, Jiang PR, Tasi SL, Chung TW, Huang YY, Liu DZ

The aim of this study was to characterize a nasally delivered bioadhesive liposome using an inactivated H5N3 virus as a model antigen. Bioadhesive liposomes were developed using tremella (T) or xanthan gum (XG) as the bioadhesive polysaccharide. Using chickens as the target animal, we evaluated whether delivery of a bioadhesive liposomal influenza vaccine via a mucosal site of infection could improve vaccine effectiveness. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) cytotoxicity assays demonstrated that T, XG and liposomes were non toxic to chicken spleen macrophages. Enzyme-linked immunosorbent assay (ELISA) was used to determine the adjuvant effect of the bioadhesive liposomal-vaccines. Chickens immunized with a low dose (200 microL) of bioadhesive liposomal influenza vaccine had significantly higher mucosal and serum antibody levels (P<0.05). In addition, liposomes mixed with a low-viscosity bioadhesive gel used for nasal delivery resulted in superior antibody responses compared with liposomes mixed with a high-viscosity gel (P<0.05). This suggest that a low-viscosity gel mixed with liposomes is more suitable for nasal delivery, and that chickens elicit higher mucosal secretory immunoglobulin A (s-IgA) and serum IgG after two vaccinations.

PMID: 19608270 [PubMed - indexed for MEDLINE]

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Electric impedance method for evaluation of the release property of calcein-encapsulated liposomes.

Colloids Surf B Biointerfaces. 2009 Nov 1;74(1):32-6

Authors: Chen G, Jiang Z, Yoshimoto M, Wei Y

This paper is concerned with the study on development of a novel method for evaluation of the liposomes release property by measuring the electric impedance changes of liposome suspensions. Calcein/NaOH encapsulated liposomes (calcein-liposomes) were prepared with deionized water and were treated with ultrasonic irradiation in order to investigate the release property of the liposomes. To validate the proposed impedance measuring method, the calcein release rates were evaluated both by the impedance changes and the fluorescence intensity changes in calcein-liposome suspensions. With the comparison of these results obtained by the two methods, it is shown that the impedance method has much wider detecting concentration range than the fluorescence one. Furthermore, the impedance method can be efficiently used for evaluation of the release property on various ionic substances encapsulated within liposomes.

PMID: 19608389 [PubMed - indexed for MEDLINE]

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Bupivacaine binding to pegylated liposomes.

Anesth Analg. 2009 Aug;109(2):678-82

Authors: Howell BA, Chauhan A

BACKGROUND: Local anesthetic drugs, such as bupivacaine, can cause severe toxicity. Lipid emulsions have been proposed and used clinically for treating such cases. Liposomes may be an alternative for overdose treatment because of their unique structures and surface charges, which allows them to act as high affinity drug "sinks" and remove bupivacaine from solution. METHODS: We conducted in vitro experiments with unilamellar and multilamellar anionic, polymer-coated liposomes to determine the amount of bupivacaine bound to liposomes in buffer solutions as a means of assessing the liposome-drug affinity. Binding experiments were also done in human serum to determine the liposomes' ability to compete with serum proteins for binding drug molecules. RESULTS: Unilamellar liposomes sequestered 60%-65% and 77%-85% of bupivacaine from buffer at 1.45 and 2.9 mg lipid/mL, respectively. The increased lipid loading increased the drug uptake at all drug concentrations measured (P = 0.001, 0.002, <0.001, and 0.003 for 5, 20, 35, and 50 microM, respectively). Multilamellar liposomes bound more drug per unit mass, with 71%-90% of the total bupivacaine bound at a phospholipid concentration of 1.45 mg lipid/mL. When comparing unilamellar and multilamellar liposomes at 1.45 mg lipid/mL, the multilamellar liposomes were significantly better at 3 of the 4 drug concentrations measured (P = 0.002, 0.001, 0.001, and 0.08 for 5, 20, 35, and 50 microM, respectively). In human serum samples, unilamellar liposomes (2.9 mg lipid/mL) reduced the unbound (free) drug by 36% (P = 0.037), 56% (P = 0.022), 47% (P = 0.042), and 50% (P = 0.018) for bupivacaine concentrations of 5, 20, 35, and 50 microM, respectively. CONCLUSIONS: The anionic, pegylated liposomes exhibit high binding for bupivacaine, both in buffer and in human serum. These results suggest that an IV injection of liposomes could be useful for the treatment of bupivacaine toxicity through drug redistribution.

PMID: 19608847 [PubMed - indexed for MEDLINE]

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Suppression of ovarian cancer growth via systemic administration with liposome-encapsulated adenovirus-encoding endostatin.

Cancer Gene Ther. 2010 Jan;17(1):49-57

Authors: Yang L, Wang L, Su XQ, Wang L, Chen XC, Li D, Luo ST, Shi HS, Chen LJ, Wang YS

Gene therapy using adenoviral vector containing the endostatin gene is a promising strategy for advanced cancers. However, host immune response to adenovirus and the lack of the requisite coxsackie-adenovirus receptor (CAR) in many primary cells limit the in vivo application. Liposome-complexed adenoviral vectors have proven to be useful for enhancing gene delivery in target cells that lack adenoviral receptors and avoiding a neutralizing antibody response. Here, we investigated antitumor effects of intravenous administration with PEG-PE cationic liposome-encapsulated recombinant human endostatin adenovirus (Ad-hEndo) on CAR-negative ovarian cancer. Electron micrography (EM) showed that these liposomes efficiently encapsulated the vectors, allowing CAR-independent adenovector transduction. The results showed that the complex enhanced transfection efficiency of recombinant adenovirus. Prolonged systemic administration was performed in immunocompetent mice and did not induce significant antibody response. The antitumor effect with PEG-PE cationic liposome encapsulated with Ad-hE (Ad-hE/lipo) was evaluated in the human ovarian cancer model. Systemic administration was well tolerated and resulted in marked suppression of tumor growth in an established ovarian cancer model, which was associated with a decreased number of micro-vessels and increased apoptosis of tumor cells. Our study shows that PEG-PE cationic liposome-encapsulated Ad-hE (Ad-hE/Lipo) can be administrated intravenously and lastingly to inhibit angiogenesis, thus showing promising clinical application.

PMID: 19609295 [PubMed - in process]

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Enhancement of transdermal delivery of phenylbutazone from liposomal gel formulations through deer skin.

J Vet Pharmacol Ther. 2009 Aug;32(4):388-92

Authors: Jayachandra Babu R, Ravis WR, Duran SH, Schumacher J, Cox E, Stahl R, Jones K, Jean Lin YJ, Phillip Lee YH, Parsons DL, Portman EM, Brown SC

Phenylbutazone (PBZ) is a nonsteroidal anti-inflammatory drug used in the treatment of chronic pain and arthritis. Topical and transdermal administration of PBZ would be beneficial in large animals in terms of minimizing gastro-intestinal ulcerations and other side effects, easy administration to legs and joints and minimizing the dose to reduce systemic toxicity of the drug. A topical liposomal preparation with different concentrations of a mono-substituted alkyl amide (MSA) and PBZ was formulated. The formulations were evaluated by in vitro skin-permeation kinetics through deer skin using Franz diffusion cells. By increasing drug loading from 1% to 5% w/w, the steady-state flux (microg/cm(2)/h) of PBZ was increased twofold (P < 0.001). Similarly, by increasing the MSA concentration from 0% to 4%, the steady-state flux (microg/cm(2)/h) of PBZ was increased twofold (P < 0.001). Overall, by increasing the drug load and the use of an appropriate amount of the penetration enhancer, the steady-state flux of PBZ through skin was increased fourfold (P < 0.001). MSA at both 2% and 4% w/w concentrations significantly increased the skin levels of PBZ as compared with control (P < 0.05). In conclusion, MSA served as an effective skin-penetration enhancer in the liposomal gel of PBZ for deer.

PMID: 19614844 [PubMed - indexed for MEDLINE]

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Antitumor activity of EGFR targeted pH-sensitive immunoliposomes encapsulating gemcitabine in A549 xenograft nude mice.

J Control Release. 2009 Nov 16;140(1):55-60

Authors: Kim IY, Kang YS, Lee DS, Park HJ, Choi EK, Oh YK, Son HJ, Kim JS

Immunoliposomes directed by monoclonal antibodies are promising vehicles for tumor targeted drug delivery. Development of a long-circulating formulation of pH-sensitive liposomes (PSLs) with epidermal growth factor receptor (EGFR) antibody attached was designed and tested using A549 cells and BALB/c-nu/nu mouse tumor model. PSL formulation was prepared using small unilamellar vesicles of DOPE and CHEMS (6:4 molar ratio) by REV method. The average size and zeta-potential of the formulation measured by dynamic laser-light scattering were approximately 146+/-43.9 nm (PDI=0.09+/-0.02) and -1.77+/-0.03 mV, respectively. A549 cells were xenotransplanted into BALB/c-nu/nu mice and various formulations of gemcitabine (gem), such as in its free form, PSLs or Ab-PSLs, were injected intravenously via a tail vein. The rate of tumor volume increment in Ab-PSLs with gem-treated group was remarkably slower than that of other drug-treated group. The tumor from Ab-PSLs with gem 160 mg/kg-injected group exhibited a markedly lowest account of PCNA labeled cells and had highest TUNEL-positive cells among tested. This suggests that treatment of Ab-PSLs with gem resulted in an increased apoptosis of tumor cells, leading to tumor growth inhibition. These results demonstrate that PSLs provide an efficient and targeted delivery of gemcitabine and may represent a useful new treatment approach for tumors which overexpress the EGFR.

PMID: 19616596 [PubMed - indexed for MEDLINE]

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Proliposomes of exemestane for improved oral delivery: formulation and in vitro evaluation using PAMPA, Caco-2 and rat intestine.

Int J Pharm. 2009 Oct 1;380(1-2):96-104

Authors: Hiremath PS, Soppimath KS, Betageri GV

The aim of the present study was to develop proliposomal formulations to enhance the oral bioavailability of exemestane by improving solubility, dissolution and/or intestinal permeability. Proliposomal powder formulations were prepared using different ratios of drug (exemestane), distearoyl-phosphatidylcholine (DSPC), cholesterol and dimyristoyl-phosphatidylglycerol (DMPG) by solvent evaporation method. The effect of phospholipid composition and drug:lipid ratio on in vitro performance of proliposomes was studied. Proliposomes were characterized for their particle size distribution, thermal characteristics by differential scanning calorimetry (DSC) and dissolution behavior. Further, the formulated proliposomes were subjected to in vitro permeation or transport studies using different models such as rat intestine, parallel artificial membrane permeability assay (PAMPA) and Caco-2 cell line. Proliposomes provided enhanced exemestane dissolution due to incorporation into the phospholipid bilayers and change in the physical state from crystalline to amorphous. The in vitro transport studies in rat intestine, PAMPA and Caco-2 models revealed that the proliposomes were successful in enhancing the permeation of exemestane. These proliposomal formulations of exemestane could provide improved oral bioavailability due to enhanced solubility, permeability and hence absorption.

PMID: 19616608 [PubMed - indexed for MEDLINE]

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[Acid-sensitive liposomes prepared with poly(ethylene glycol)-POPA derivatives]

Yao Xue Xue Bao. 2009 May;44(5):519-24

Authors: Wang Z, Wang RT, Liu Q, Chen T

The poly(ethylene glycol)-lipid derivatives were synthesized for constructing pH-sensitive liposomes. The polyethylene glycol polymer MePEG2000-NH2 and phospholipids POPA were connected by phosphorus-amide linkage. The poly(ethylene glycol)-lipid derivatives acidic sensitive liposomes were prepared. Factor effects on polymer insertion into liposomes were evaluated and the pH-sensitivity of the polymer associated liposomes were studied by calcein release assay. The poly(ethylene glycol)-lipid derivatives acidic sensitive liposomes were prepared successfully by the extruding linkage device. The liposomes constructing by poly(ethylene glycol)-lipid derivatives was stable at pH 6.5-7.5, the stability was closely related to phospholipid types and cholesterol content of the preparation of liposomes. At pH 5.0 occurred when divulging fluorescence occurred obviously, the leakage rate and the strength was with a positive correlation between time of in the acidic environment and intensity of acid. The acidic sensitive liposomes prepared by poly(ethylene glycol)-lipid derivatives were developed as a potential pH sensitive delivery system.

PMID: 19618730 [PubMed - indexed for MEDLINE]

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[Comparison of two kinds of cationic vectors-mediated gene delivery]

Yao Xue Xue Bao. 2009 May;44(5):553-7

Authors: Zhi DF, Wang B, Cui SH, Yang BL, Zhao BD, Zhao YN, Jiang YX, Yu SJ, Zhang SB

In order to study the important factors involved in cationic liposome-mediated gene transfer, Lipofectamine 2000 or DOTAP was evaluated using three types of cells (Hep-2, MCF-7 and SW-480) in vitro transfection efficiencies. Different properties of the two reagents were analyzed and compared by DNA arrearage assay and MTT assay. Both Lipofectamine 2000 and DOTAP had strong capability to combine with DNA; Lipofectamine 2000 can get higher transfection efficiency of the three cells by using GFP as report gene, meanwhile, DOTAP can also get higher transfection efficiency against Hep-2 cell. However, DOTAP showed lower transfection efficiency against MCF-7 and SW-480 cell. On the other hand, the cytotoxicity assay showed that over 85% cell viability of MCF-7 cell could be achieved both by Lipofectamine 2000 and DOTAP under the optimal transfection condition. Relatively speaking, Lipofectamine 2000 has very high transfection efficiency in a broad range of cell lines, but because of the special selectivity of cell type on liposome, DOTAP also has a broad application prospect.

PMID: 19618735 [PubMed - indexed for MEDLINE]

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Hydration effects on skin microstructure as probed by high-resolution cryo-scanning electron microscopy and mechanistic implications to enhanced transcutaneous delivery of biomacromolecules.

J Pharm Sci. 2010 Feb;99(2):730-40

Authors: Tan G, Xu P, Lawson LB, He J, Freytag LC, Clements JD, John VT

Although hydration is long known to improve the permeability of skin, penetration of macromolecules such as proteins is limited and the understanding of enhanced transport is based on empirical observations. This study uses high-resolution cryo-scanning electron microscopy to visualize microstructural changes in the stratum corneum (SC) and enable a mechanistic interpretation of biomacromolecule penetration through highly hydrated porcine skin. Swollen corneocytes, separation of lipid bilayers in the SC intercellular space to form cisternae, and networks of spherical particulates are observed in porcine skin tissue hydrated for a period of 4-10 h. This is explained through compaction of skin lipids when hydrated, a reversal in the conformational transition from unilamellar liposomes in lamellar granules to lamellae between keratinocytes when the SC skin barrier is initially established. Confocal microscopy studies show distinct enhancement in penetration of fluorescein isothiocyanate-bovine serum albumin (FITC-BSA) through skin hydrated for 4-10 h, and limited penetration of FITC-BSA once skin is restored to its natively hydrated structure when exposed to the environment for 2-3 h. These results demonstrate the effectiveness of a 4-10 h hydration period to enhance transcutaneous penetration of large biomacromolecules without permanently damaging the skin.

PMID: 19582754 [PubMed - indexed for MEDLINE]

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Evaluation of encapsulated Newcastle disease virus liposomes using various phospholipids administered to improve chicken humoral immunity.

J Biomed Mater Res B Appl Biomater. 2009 Nov;91(2):621-5

Authors: Tseng LP, Chiou CJ, Deng MC, Lin MH, Pan RN, Huang YY, Liu DZ

We propose the adjuvant effects of phospholipid liposome compositions using intranasal inoculation of a liposomal-Newcastle disease virus (NDV) vaccine in chickens. The immunogenicity of three liposome formulations was determined in chickens using the hemagglutination-inhibition (HI) test, nasal secretory immunoglobulin A and serum immunoglobulin A (IgG) antibody titers using the enzyme-linked immunosorbent assay. The immune response against NDV antigens was determined after immunization with neutral charged liposomes composed of egg phosphatidylcholine (EPC) (60 micromol), cholesterol (Chol) (15 micromol), and EPC-liposomes (EPC-Lip), which elicited strong systemic (serum) and local (nasal) humoral responses. However, the intranasal administration with cationic charged liposomes composed of EPC (30 micromol), stearylamine (SA) (15 micromol), Chol (15 micromol), and SA-liposomes (SA-Lip) induced poor humoral immune responses. Only the vaccine formulated with anionic charged liposomes composed of EPC (30 micromol), dipalmitoylphosphatidylserine (15 micromol), Chol (15 micromol), and phosphatidylserine-liposomes (PS-Lip) elicited the highest titers of HI antibodies. These are the first results to suggest that antigen delivery using EPC-Lip is very useful in enhancing antibody production at the mucosal site and in serum.

PMID: 19582853 [PubMed - indexed for MEDLINE]

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FLEth RNA intercalating probe is a convenient reporter for small interfering RNAs.

J Am Chem Soc. 2009 Jul 29;131(29):9872-3

Authors: van der Wiel IM, Cheng J, Koukiekolo R, Lyn RK, Stevens N, O'Connor N, Turro NJ, Pezacki JP

Here we report that the phenanthridine derivative covalently linked to a fluorescein moiety (FLEth) can act as a fluorescence based probe for duplex short interfering RNA (siRNA) and that this probe can also be used to report on protein-RNA interactions. A fluorescence resonance energy transfer (FRET) signal that is observed at 600 nm occurs when FLEth is complexed with siRNA. At least 2 molecules of FLEth can bind to 21 nt duplex siRNA, and the dissociation constants for these interactions are reported. We find that FLEth can also report on the interaction of siRNAs with the Carnation Italian ringspot viral suppressor of RNA silencing p19. FLEth does not bind to the siRNA-p19 complex nor can p19 bind to the siRNA-FLEth complex; rather FLEth can report on the fraction of siRNA that is unbound. FLEth can also bind siRNA in delivery systems such as liposomes. Once the siRNA reaches the interior of Huh 7.5 cells, FLEth dissociates from the siRNA and is found in the nucleoli suggesting that FLEth cannot bind to siRNAs that are associated with the RNA silencing machinery.

PMID: 19583254 [PubMed - indexed for MEDLINE]

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Expression of endostatin mediated by a novel non-viral delivery system inhibits human umbilical vein endothelial cells in vitro.

Mol Biol Rep. 2010 Apr;37(4):1755-62

Authors: Zhang C, Zhang X, Liu C, Wang J, Liu X, Li H, Wang J, Wu C

Ultrasound (US)-mediated microbubble destruction is recognized to have considerable potential for gene delivery, whereas, there is few report of its effect on enhancing liposomal transfection. In this study, we used pIRES2-EGFP/hES containing human endostatin (hES) cDNA as target gene to test the hypothesis that US exposure with microbubbles could improve liposomal transfection, and to investigate the possibility of intracellular delivery of ES gene using this method. Under the controlled US exposure condition with microbubbles, the plasmid:liposome was transferred into COS-7 cells. The transfection rate, the expression of endostatin and the inhibition effect of transfection-endostatin on endothelial cells were assessed. The results revealed that US-mediated microbubble destruction together with liposome could significantly enhance gene transfection without obvious cell damage. By this means, endostatin gene could be efficiently transferred into COS-7 cells and expressed. The transfection-endostatin could inhibit endothelial proliferation and migration, which suggests that the non-viral method might be useful in anti-angiogenesis therapy in the future.

PMID: 19585274 [PubMed - in process]

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Penetration enhancer-containing vesicles (PEVs) as carriers for cutaneous delivery of minoxidil.

Int J Pharm. 2009 Oct 1;380(1-2):72-9

Authors: Mura S, Manconi M, Sinico C, Valenti D, Fadda AM

The aim of this work was to evaluate the ability of a few different penetration enhancers to produce elastic vesicles with soy lecithin and the influence of the obtained vesicles on in vitro (trans)dermal delivery of minoxidil. To this purpose, so-called Penetration Enhancer-containing Vesicles (PEVs) were prepared as dehydrated-rehydrated vesicles by using soy lecithin and different amounts of three penetration enhancers, 2-(2-ethoxyethoxy)ethanol (Transcutol), capryl-caproyl macrogol 8-glyceride (Labrasol), and cineole. Soy lecithin liposomes, without penetration enhancers, were used as control. Prepared formulations were characterized in terms of size distribution, morphology, zeta potential, and vesicle deformability. The influence of PEVs on (trans)dermal delivery of minoxidil was studied by in vitro diffusion experiments through newborn pig skin in comparison with traditional liposomes and ethanolic solutions of the drug also containing each penetration enhancer. A skin pre-treatment study using empty PEVs and conventional liposomes was also carried out. Results showed that all the used penetration enhancers were able to give more deformable vesicles than conventional liposomes with a good drug entrapment efficiency and stability. In vitro skin penetration data showed that PEVs were able to give a statistically significant improvement of minoxidil deposition in the skin in comparison with classic liposomes and penetration enhancer-containing drug ethanolic solutions without any transdermal delivery. Moreover, the most deformable PEVs, prepared with Labrasol and cineole, were also able to deliver to the skin a higher total amount of minoxidil than the PE alcoholic solutions thus suggesting that minoxidil delivery to the skin was strictly correlated to vesicle deformability, and therefore to vesicle composition.

PMID: 19589377 [PubMed - indexed for MEDLINE]

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Nanoparticles evading the reticuloendothelial system: role of the supported bilayer.

Biochim Biophys Acta. 2009 Oct;1788(10):2259-66

Authors: Li SD, Huang L

We have previously shown that the PEGylated LPD (liposome-polycation-DNA) nanoparticles were highly efficient in delivering siRNA to the tumor with low liver uptake. Its mechanism of evading the reticuloendothelial system (RES) is reported here. In LPD, nucleic acids were condensed with protamine into a compact core, which was then coated by two cationic lipid bilayers with the inner bilayer stabilized by charge-charge interaction (also called the supported bilayer). Finally, a detergent-like molecule, polyethylene glycol (PEG)-phospholipid is post-inserted into the lipid bilayer to modify the surface of LPD. The dynamic light scattering (DLS) data showed that LPD had improved stability compared to cationic liposomes after incubation with a high concentration of DSPE-PEG(2000), which is known to disrupt the bilayer. LPD prepared with a multivalent cationic lipid, DSGLA, had enhanced stability compared to those containing DOTAP, a monovalent cationic lipid, suggesting that stronger charge-charge interaction in the supported bilayer contributed to a higher stability. Distinct nanoparticle structure was found in the PEGylated LPD by transmission electron microscopy, while the cationic liposomes were transformed into tubular micelles. Size exclusion chromatography data showed that approximately 60% of the total cationic lipids, which were located in the outer bilayer of LPD, were stripped off during the PEGylation; and about 20% of the input DSPE-PEG(2000) was incorporated into the inner bilayer with about 10.6 mol% of DSPE-PEG(2000) presented on the particle surface. This led to complete charge shielding, low liver sinusoidal uptake, and 32.5% injected dose delivered to the NCI-H460 tumor in a xenograft model.

PMID: 19595666 [PubMed - indexed for MEDLINE]

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Convenient targeting of stealth siRNA-lipoplexes to cells with chelator lipid-anchored molecules.

J Control Release. 2009 Nov 3;139(3):229-38

Authors: Herringson TP, Altin JG

A major obstacle for the use of siRNAs as novel therapeutics is the requirement for functional delivery to specific cells in vivo. siRNA delivery by cationic agents is generally non-specific and a convenient targeting strategy has been lacking. This work explored the potential for using the chelator lipid 3(nitrilotriacetic acid)-ditetradecylamine (NTA(3)-DTDA) with neutral stealth liposomes to target siRNA to cells. A novel method for incorporating siRNAs into lipoplexes was developed which utilised helper lipids and the ionisable lipid 1,2-dioleoyl-3-dimethylammonium-propane (DODAP). This approach results in an efficient (>50%) incorporation of siRNA into lipoplexes, which when incorporated with Ni-NTA(3)-DTDA and engrafted with a His-tagged form of murine CD4 can target siRNA to murine A20 B cells, in vitro. Also, siRNA-lipoplexes engrafted with His-tagged peptides that target receptors on HEK-293 cells, or the receptor for tumour necrosis factor alpha expressed on the murine dendritic cell line DC2.4, could target siRNA and silence the expression of enhanced green fluorescence protein (EGFP). siRNA-lipoplexes produced by this method are approximately 240 nm dia, exhibit low zeta-potential (-1 mV), and target cells in serum-containing media. The results show that NTA(3)-DTDA can be used to target siRNA-lipoplexes to cells, and could provide a convenient approach for targeting siRNA to cells in vivo for therapeutic applications.

PMID: 19595724 [PubMed - indexed for MEDLINE]

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Cryo-electron tomography of nanoparticle transmigration into liposome.

J Struct Biol. 2009 Dec;168(3):419-25

Authors: Le Bihan O, Bonnafous P, Marak L, Bickel T, Trépout S, Mornet S, De Haas F, Talbot H, Taveau JC, Lambert O

Nanoparticle transport across cell membrane plays a crucial role in the development of drug delivery systems as well as in the toxicity response induced by nanoparticles. As hydrophilic nanoparticles interact with lipid membranes and are able to induce membrane perturbations, hypothetic mechanisms based on membrane curvature or hole formation have been proposed for activating their transmigration. We report on the transport of hydrophilic silica nanoparticles into large unilamellar neutral DOPC liposomes via an internalization process. The strong adhesive interactions of lipid membrane onto the silica nanoparticle triggered liposome deformation until the formation of a curved neck. Then the rupture of this membrane neck led to the complete engulfment of the nanoparticle. Using cryo-electron tomography we determined 3D architectures of intermediate steps of this process unveiling internalized silica nanoparticles surrounded by a supported lipid bilayer. This engulfing process was achieved for a large range of particle size (from 30 to 200 nm in diameter). These original data provide interesting highlights for nanoparticle transmigration and could be applied to biotechnology development.

PMID: 19596070 [PubMed - indexed for MEDLINE]

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Release of liposomal contents by cell-secreted matrix metalloproteinase-9.

Bioconjug Chem. 2009 Jul;20(7):1332-9

Authors: Banerjee J, Hanson AJ, Gadam B, Elegbede AI, Tobwala S, Ganguly B, Wagh AV, Muhonen WW, Law B, Shabb JB, Srivastava DK, Mallik S

Liposomes have been widely used as a drug delivery vehicle, and currently, more than 10 liposomal formulations are approved by the Food and Drug Administration for clinical use. However, upon targeting, the release of the liposome-encapsulated contents is usually slow. We have recently demonstrated that contents from appropriately formulated liposomes can be rapidly released by the cancer-associated enzyme matrix metalloproteinase-9 (MMP-9). Herein, we report our detailed studies to optimize the liposomal formulations. By properly selecting the lipopeptide, the major lipid component, and their relative amounts, we demonstrate that the contents are rapidly released in the presence of cancer-associated levels of recombinant human MMP-9. We observed that the degree of lipid mismatch between the lipopepides and the major lipid component profoundly affects the release profiles from the liposomes. By utilizing the optimized liposomal formulations, we also demonstrate that cancer cells (HT-29) which secrete low levels of MMP-9 failed to release a significant amount of the liposomal contents. Metastatic cancer cells (MCF7) secreting high levels of the enzyme rapidly release the encapsulated contents from the liposomes.

PMID: 19601658 [PubMed - indexed for MEDLINE]

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Liposome-hydrogel bead complexes prepared via biotin-avidin conjugation.

Langmuir. 2009 Aug 18;25(16):9413-23

Authors: MacKinnon N, Guérin G, Liu B, Gradinaru CC, Macdonald PM

Liposomes immobilized onto polymeric hydrogel microbeads have potential advantages both in tissue engineering applications and as drug delivery vehicles. Here we demonstrate, quantify, and optimize lipid vesicle binding to polymeric hydrogel microbeads via the avidin-biotin conjugation system and characterize the stability of the resulting microgel-bound liposomes. Microgels consisting of a copolymer of N-isopropylacrylamide (NIPAM) and acrylic acid (AA), cross-linked with bis-acrylamide, that is, p(NIPAM-co-AA), were biotinylated using aqueous carbodiimide chemistry. Extruded liposomes consisting of 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) plus a small fraction of a biotin-derivatized phosphatidylethanolamine (B-PE) were saturated with avidin and allowed to bind to biotinylated hydrogel beads. Using a combination of fluorescence spectroscopy, quenching, and microscopy and 31P NMR static and magic angle spinning (MAS) spectroscopies, we demonstrate conditions for near-quantitative liposome binding to p(NIPAM-co-AA) microbeads and show that liposome fusion does not occur under such conditions, that the liposomes remain intact and impermeable when so bound, and that they can function as slow release vehicles for entrapped aqueous species.

PMID: 19603800 [PubMed - indexed for MEDLINE]

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Arsonoliposomes for the potential treatment of medulloblastoma.

Pharm Res. 2009 Oct;26(10):2237-46

Authors: Favretto ME, Marouf S, Ioannou P, Antimisiaris SG, Parker TL, Kallinteri P

PURPOSE: To investigate the arsonoliposome effect on medulloblastoma cells (VC312Rs) related to uptake, endocytotic mechanism and cell viability. METHODS: VC312R viability in presence of either arsonoliposomes or stealth liposomes was studied using MTT assay for 1-4 days. Fibroblasts (3T3) were used as control. Apoptosis was studied for 2 h, 5 h and 24 h. Bodipy-labelled arsonoliposome uptake (time- and dose-dependent) was estimated using FACS analysis. The endocytotic mechanism was investigated using inhibitors of clathrin- (chlorpromazine) and caveolae-mediated endocytosis (filipin). RESULTS: Arsonoliposomes affected significantly the VC312R viability compared to 3T3 cells and induced apoptosis to VC312Rs after 2 h of incubation. Apoptosis was not observed for 3T3 cells. Liposome uptake versus time showed a bimodal pattern. Clathrin-mediated endocytosis was the main endocytotic mechanism at low lipid concentrations and caveolae at higher ones; thus, dose-dependent uptake did not show a plateau at increased lipid concentrations. CONCLUSIONS: Arsonoliposomes showed "selective" toxicity towards medulloblastoma cells inducing apoptosis after 2 hs of incubation. Therefore, arsonoliposomes are promising anticancer vehicles for brain tumour treatment.

PMID: 19626426 [PubMed - indexed for MEDLINE]

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[Comparison of in vitro release behavior of proanthocyanidins flexible nanoliposomes and general nanoliposomes]

Zhongguo Zhong Yao Za Zhi. 2010 Jan;35(2):169-72

Authors: Chen Y, Wu H, Yuan J, Shi L, Jin R, Liu H, Xiong W, Huang L

OBJECTIVE: To prepare flexible proanthocyanidins nanoliposomes, and explore the in vitro release behavior of proanthocyanidins flexible nanoliposomes and general nanoliposomes. METHOD: Flexible proanthoeyanidins nanoliposomes were prepared proanthocyanidins using a film dispersion method, characterized by transmission electron microscope, and the in vitro release action was studied in different dissolution mediums using dynamic dialyse method with the content of total phenol as index. RESULT: The in vitro release of both proanthocyanidins flexible nanoliposomes and general nanoliposomes were in accordance with Weibull distribution. CONCLUSION: Proanthocyanidins flexible nanoliposomes without pressure had similar in vitro release behavior with general nanoliposomes.

PMID: 20394286 [PubMed - indexed for MEDLINE]

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Palmitoyl Ascorbate-Modified Liposomes as Nanoparticle Platform for Ascorbate-Mediated Cytotoxicity and Paclitaxel Co-delivery.

Eur J Pharm Biopharm. 2010 Apr 27;

Authors: Sawant RR, Vaze O, Rockwell K, Torchilin VP

Ascorbate has multiple biological roles and chemical interactions, some of which differ between normal and cancerous tissues. Biological effects of ascorbate depend on concentration, route of exposure, and duration of exposure. High dose ascorbate acts as a pro-oxidant in tissue fluids and delivers peroxide to tissues and fluids which is then detoxified by erythrocytes and plasma catalase in normally perfused areas. We have previously shown that nanoparticles incorporating palmitoyl ascorbate (PA) targeted and killed cancer cells in vitro. Here, our studies provide additional indications of the importance of extracellular reactive oxygen species (ROS) in the anti-cancer-toxicity by PA liposomes. Cell death in vitro can be blocked by catalase, superoxide dismutase, and the thiol reductant TCEP. Intracellullar iron may also play a role. Iron chelation by desferrioxamine inhibited cell death but EDTA did not. Further, the fluorescent marker of ROS production in cells indicated that the PA liposomes caused an increase in ROS. Fluorescent microscopy of tumor sections taken at 3 hours after injection of rhodamine-labeled liposomes demonstrated an increased accumulation of PA-liposomes compared to plain liposomes. However, the overall biodistribution of (111)In labeled PA-liposomes was similar to plain liposomes. PA liposomes provided substantial anti-tumor activity in vivo and enhanced the anti-cancer activity of liposomally encapsulated paclitaxel. Thus, nanoparticles incorporating PA provide a platform for enhancement of the anti-tumor activity of ascorbate.

PMID: 20433922 [PubMed - as supplied by publisher]

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Distearoylphosphatidylethanolamine based liposomes for ultrasound-mediated drug delivery.

Eur J Pharm Biopharm. 2010 Apr 28;

Authors: Evjen TJ, Nilssen EA, Rögnvaldsson S, Brandl M, Fossheim SL

The ability of ultrasound (US) to permeabilize phospholipid membranes has opened the potential of using US as a means to enhance delivery of anti-cancer drugs to tumour cells via liposomes. In this study novel US sensitive or sonosensitive doxorubicin-containing liposomes based on 1,2 distearoyl-sn-glycero-3-phosphatidylethanolamine (DSPE) as the main lipid component are reported. A variety of lipid bilayer compositions was studied with respect to in vitro US triggered release of liposomal drug as well as serum stability in terms of drug retention, using experimental design. The multivariate data analysis indicated a strong correlation between DSPE content and sonosensitivity, both alone and in interplay with cholesterol. The most optimal formulation showed approximately 70% release of doxorubicin after 6 min of US exposure. This represented a 7- fold increase in release extent as compared to standard pegylated liposomal doxorubicin. The significant enhancement in sonosensitivity of the liposomes shows the potential of engineering liposomal lipid composition for US-mediated drug delivery. Abbrevations: US, ultrasound; Chol, Cholesterol; DSPE, 1 *2 distearoyl-sn-glycero-3-phosphatidylethanolamine; DSPE-PEG, 1 *2 distearoyl-sn-glycero-3-phosphatidylethanolamine-N-(methoxy(polyethylene glycol)-2000); DSPC, 1 *2 distearoyl-sn-glycero-3-phosphatidylcholine; HSPC, hydrogenated (soy) L-alpha-phosphatidylcholine; DXR, doxorubicin; PE, phosphatidylethanolamine; L(alpha), lamellar liquid-crystalline phase; H(II), inverted hexagonal phase.

PMID: 20434558 [PubMed - as supplied by publisher]

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Ocular Drug Delivery.

AAPS J. 2010 May 1;

Authors: Gaudana R, Ananthula HK, Parenky A, Mitra AK

Ocular drug delivery has been a major challenge to pharmacologists and drug delivery scientists due to its unique anatomy and physiology. Static barriers (different layers of cornea, sclera, and retina including blood aqueous and blood-retinal barriers), dynamic barriers (choroidal and conjunctival blood flow, lymphatic clearance, and tear dilution), and efflux pumps in conjunction pose a significant challenge for delivery of a drug alone or in a dosage form, especially to the posterior segment. Identification of influx transporters on various ocular tissues and designing a transporter-targeted delivery of a parent drug has gathered momentum in recent years. Parallelly, colloidal dosage forms such as nanoparticles, nanomicelles, liposomes, and microemulsions have been widely explored to overcome various static and dynamic barriers. Novel drug delivery strategies such as bioadhesive gels and fibrin sealant-based approaches were developed to sustain drug levels at the target site. Designing noninvasive sustained drug delivery systems and exploring the feasibility of topical application to deliver drugs to the posterior segment may drastically improve drug delivery in the years to come. Current developments in the field of ophthalmic drug delivery promise a significant improvement in overcoming the challenges posed by various anterior and posterior segment diseases.

PMID: 20437123 [PubMed - as supplied by publisher]

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Cytoplasmic Delivery of Liposomes into MCF-7 Breast Cancer Cells Mediated by Cell-Specific Phage Fusion Coat Protein.

Mol Pharm. 2010 May 3;

Authors: Wang T, Yang S, Petrenko VA, Torchilin V

Earlier, we have shown that doxorubicin-loaded liposomes (Doxil) modified with a chimeric phage fusion coat protein specific towards MCF-7 breast cancer cells identified from a phage landscape library demonstrated a significantly enhanced association with target cells and an increased cytotoxicity. Based on some structural similarities between the N-terminus of the phage protein and known fusogenic peptides, we hypothesized that, in addition to the specific targeting, the phage protein may possess endosome-escaping potential and an increased cytotoxicity of drug-loaded phage protein-targeted liposomes may be explained by an advantageous combination of both, cell targeting and endosomal escape of drug-loaded nanocarrier. The use of the fluorescence resonance energy transfer (FRET) technique allowed us to clearly demonstrate the pH-dependent membrane fusion activity of the phage protein. Endosomal escape and cytosolic delivery of phage-liposomes was visualized with fluorescence microscopy. Endosome acidification inhibition by bafilomycin A 1 resulted in decreased cytotoxicity of the phage-Doxil, while the endosome disruption by chloroquine had a negligible effect on efficacy of phage-Doxil, confirming its endosomal escape. Our results demonstrated an endosome-escaping property of the phage protein and provided an insight on mechanism of the enhanced cytotoxicity of phage-Doxil.

PMID: 20438086 [PubMed - as supplied by publisher]

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Improvement of targeted gene delivery to human cancer cells by a novel trifunctional crosslinker.

Chem Asian J. 2009 Aug 3;4(8):1318-22

Authors: Shiota M, Shamsur L, Kawahara S, Wadhwa R, Ikeda Y

A facile method for the construction of an immunoconjugate which displays targeting ligands, such as antibody fragments, with a high density is reported. For this purpose, we synthesized a novel trifunctional crosslinking reagent. By the use of this reagent, ligands targeting the specific cell can be displayed on the surface of the drug carrier with a high density. In this study, we display HER2 (human epidermal growth-factor receptor-2) binding ligands on branched polyethylenimine (PEI), which can form polyplexes with plasmid DNA. Kinetic analysis of the binding to the extracellular domain of HER2 show the PEI displaying a high density of ligands binds to the target more strongly compared to the PEI displaying ligands at a low density. The increased density of HER2 ligands displayed on the gene carrier contributes to the improved transfection efficiency. This approach can be applied to other drug delivery systems, including liposome, micelle, and so on.

PMID: 19579256 [PubMed - indexed for MEDLINE]

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Ethosomes: a novel delivery system for antifungal drugs in the treatment of topical fungal diseases.

Indian J Exp Biol. 2009 May;47(5):368-75

Authors: Bhalaria MK, Naik S, Misra AN

Aim of this work was to prepare and characterize fluconazole (FLZ) encapsulated ethosomes, incorporate it in suitable dermatological base, and asses its comparative clinical efficacy in the treatment of Candidiasis patients against liposomal gel, marketed product and hydroethanolic solution of the drug. Drug encapsulated ethosomes and liposomes were prepared and optimized by "Hot" method technique and lipid film hydration technique. Vesicular carriers were characterized for % entrapment efficiency, particle size and shape, in vitro drug diffusion study, mean % reduction in dimension of Candidiasis lesion and stability study by using suitable analytical technique. Vesicle size and drug entrapment efficiency of the optimized ethosomes and liposomes were found to be 144 +/- 6.8 nm and 82.68% and 216 +/- 9.2 nm and 68.22% respectively. Microscopic examinations suggest ethosomes to be multilamellar spherical vesicles with a smooth surface. The differential scanning calorimetry results suggest high fluidity of the ethosomes than liposomes. In vitro drug diffusion studies demonstrated that % drug diffused from ethosomes was nearly twice than liposomes and three times higher than the hydroethanolic solution across rat skin. From the clinical evaluation, the developed novel delivery system demonstrated enhanced antifungal activity compared to liposomal formulation, marketed formulation and hydroethanolic solution of the drug.

PMID: 19579803 [PubMed - indexed for MEDLINE]

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Generation of liposome aerosols with the Aeroneb Pro and the AeroProbe nebulizers.

J Liposome Res. 2009 Jul 6;

Authors: Gaspar MM, Gobbo O, Ehrhardt C

Background: Inhalation of therapeutic aerosols is a long-established means of drug delivery to the lungs or to the systemic circulation. In addition to solutions, suspensions, and particulates, liposomal formulations are being developed for aerosol administration. In this report, we investigated the membrane integrity of liposomes encapsulating the fluorescent model compound, calcein, after nebulization using two novel aerosolization devices, the Aeroneb Pro vibrating-mesh nebulizer (Aerogen, Dangan, Ireland) and the AeroProbe intracorporeal nebulizing catheter (Trudell Medical Corporation, London, Ontario, Canada). Materials and Methods: The influence of lipid composition and lamellarity on the stability of the vesicles was investigated by measuring changes in median diameter, zeta-potential, and calcein retention. Results: Both nebulizers were able to successfully aerosolise 1.5 mL of liposome suspension in a short period of time. The diameter and zeta-potential of the liposomes was preserved upon nebulization, and the calcein retention was above 70% in all cases. Conclusions: It can, hence, be concluded that both systems, the Aeroneb Pro and the AeroProbe, are well suited for the pulmonary delivery of liposomal formulations, with the AeroProbe having the additional advantage of allowing targeted delivery into the select regions of the lungs with a high degree of efficiency and control.

PMID: 19580376 [PubMed - as supplied by publisher]

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A method for oral administration of hydrophilic substances to Caenorhabditis elegans: Effects of oral supplementation with antioxidants on the nematode lifespan.

Mech Ageing Dev. 2009 Sep;130(9):652-5

Authors: Shibamura A, Ikeda T, Nishikawa Y

Numerous studies using Caenorhabditis elegans have used a protocol in which chemicals are orally delivered by incorporating them into the nematode growth media or mixing them with the food bacteria. However, actual exposure levels are difficult to estimate as they are influenced by both the rates of ingestion into the intestine as well as absorption from the intestinal lumen. We used liposomes loaded with the hydrophilic fluorescent reagent uranin to test oral administration of water-soluble substances to C. elegans. Ingestion of liposomes loaded with fluorescent dye resulted in successful oral delivery of chemicals into the intestines of C. elegans. Using liposomes, oral administration of hydrophilic antioxidants (ascorbic acid, N-acetyl-cysteine, reduced glutathione, and thioproline) prolonged the lifespan of the nematodes, whereas the conventional method of delivery showed neither fluorescence nor longevity effects. Our method efficiently and quantitatively delivers solutes to nematodes.

PMID: 19580823 [PubMed - indexed for MEDLINE]

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Pegylated nanoliposomes remote-loaded with the antioxidant tempamine ameliorate experimental autoimmune encephalomyelitis.

J Neuroimmunol. 2009 Aug 18;213(1-2):20-5

Authors: Kizelsztein P, Ovadia H, Garbuzenko O, Sigal A, Barenholz Y

Reactive oxygen species are involved in the pathogenesis of multiple sclerosis (MS), Parkinson's disease and neurodegenerative diseases. Here we report that Tempamine (TMN), a stable radical with antioxidant and proapoptotic activities, when encapsulated in the intraliposome aqueous phase of pegylated (<100 nm) nanoliposomes (nSSL), is efficient in inhibiting experimental autoimmune encephalomyelitis (EAE) in mice. The TMN is remote-loaded into nSSL by an intraliposome high/extraliposome low transmembrane ammonium sulfate gradient. Biodistribution studies of nSSL-TMN labeled with the liposome non transferable non metabolizable (3)H-cholesteryl hexadecyl ether show that almost 3% of the injected dose of liposomes reached the brain of the EAE mice, compared with less than 1% in the control healthy mice. This accumulation in the brain, combined with the fact that TMN demonstrates a controlled slow release out of the nSSL, may explain the superior therapeutic activity of nSSL-TMN over free TMN. Our results suggest that the study of nSSL-TMN for therapy of MS, and other neurodegenerative diseases involving oxidative damage, is worth pursuing.

PMID: 19564052 [PubMed - indexed for MEDLINE]

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Preparation of pegylated nano-liposomal formulation containing SN-38: In vitro characterization and in vivo biodistribution in mice.

Acta Pharm. 2009 Jun;59(2):133-44

Authors: Atyabi F, Farkhondehfai A, Esmaeili F, Dinarvand R

7-Ethyl-10-hydroxy-camptothecin (SN-38), a metabolite of irinotecan x HCl, is poorly soluble in aqueous solutions and practically insoluble in most physiologically compatible and pharmaceutically acceptable solvents. Formulation of SN-38 in concentrated pharmaceutical delivery systems for parenteral administration is thus very difficult. Due to their biocompatibility and low toxicity, liposomes were considered for the delivery of SN-38. In this study, pegylated liposomes with distearoylphosphatidylcholine, distearoylphosphatidylethanolamine containing SN-38 were prepared and their characteristics, such as particle size, encapsulation efficiency, in vitro drug release and biodistribution, were investigated. The particle size of liposomes was in the range of 150--200 nm. The encapsulation efficiency and in vitro release rate of pegylated liposomes was higher than those of non-pegylated liposomes. As expected, the distribution of pegylated liposomes in body organs such as liver, kidney, spleen and lung was considerably lower than that of non-pegylated liposomes. Also, their blood concentration was at least 50 % higher than that of non-pegylated liposomes.

PMID: 19564139 [PubMed - indexed for MEDLINE]

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Using in vivo biopanning for the development of radiation-guided drug delivery systems.

Methods Mol Biol. 2009;542:285-300

Authors: Jaboin JJ, Han Z, Hallahan DE

This chapter illustrates our protocol for in vivo biopanning using T7 bacteriophage libraries for the purpose of selecting recombinant peptides for the tumor-specific delivery of radiosensitizers to radiation-inducible antigens within tumor neovasculature. Our goal is to discover peptides binding within tumor vascular endothelium of irradiated tumors. We have previously demonstrated that tumor irradiation increases the spectrum of antigenic targets for drug delivery. To identify candidate peptides with the ability to bind radiation-induced antigens, we inject the phage peptide library intravenously into mice bearing irradiated GL261 and Lewis lung carcinoma (LLC) hind limb tumors. Phage are recovered from excised tumors, amplified, and readministered to mouse-bearing tumors for six total rounds. At least 50 bacterial colonies are selected from each of the tumor types, and prioritized. This prioritization is based on their relative concentrations in tumor versus normal tissues, and then assessment of dominant phage present in both tumor types. These phage are amplified, and the gene sequences determined to deduce the recombinant peptide product. Further prioritization is performed by fluorescence labeling of the selected phage, and injection into irradiated and mock-irradiated tumor-bearing mice for evaluation of in vivo targeting of the candidate phage/peptides.

PMID: 19565908 [PubMed - indexed for MEDLINE]

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Anionic amino acid-derived cationic lipid for siRNA delivery.

J Control Release. 2009 Dec 16;140(3):268-76

Authors: Suh MS, Shim G, Lee HY, Han SE, Yu YH, Choi Y, Kim K, Kwon IC, Weon KY, Kim YB, Oh YK

Viable siRNA therapeutic strategies require the concurrent development of effective and safe delivery systems. Here, we described the synthesis of a new cationic lipid, N,N''-dioleylglutamide (DG), and evaluated DG-based liposomes as an siRNA delivery system. DG, an amino acid derivative, was synthesized by peptide bond linkage of oleylamine to each carboxylic acid group of glutamic acid. Gel retardation assays showed that DG-based cationic liposomes and siRNA began to form complexes from the N/P ratio of 1.8. The viability of A549, HeLa and WM266.4 cells was significantly higher after treatment with DG-based liposomes than with Lipofectamine 2000 and cationic 3beta-[N-(N',N'-dimethylaminoethane)-carbamoyl] cholesterol (DC-Chol)-based liposomes. The DG-based cationic liposomes could effectively deliver a fluorescent model siRNA into A549, HeLa, and WM266.4 human cancer cell lines, showing at least 2-fold higher fluorescence mean intensity values than did Lipofectamine 2000. When survivin-specific siRNA was delivered to cells in lipoplexes, survivin mRNA levels were reduced by DG-based liposomes to the higher extent than Lipofectamine 2000 and DC-Chol-based liposomes. When red fluorescent protein (RFP)-expressing cells were treated with RFP-specific siRNA (siRFP), RFP expression significantly decreased in cells treated with DG-based liposomes. Molecular imaging revealed that intratumoral injection of siRFP and DG-based liposome complexes significantly reduced fluorescence in RFP-expressing tumor tissues in mice. These results suggest that DG-based cationic liposomes would be of value for cellular delivery and in vivo local delivery of siRNA.

PMID: 19567256 [PubMed - indexed for MEDLINE]

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Folate-mediated intracellular drug delivery increases the anticancer efficacy of nanoparticulate formulation of arsenic trioxide.

Mol Cancer Ther. 2009 Jul;8(7):1955-63

Authors: Chen H, Ahn R, Van den Bossche J, Thompson DH, O'Halloran TV

Arsenic trioxide (As(2)O(3)) is a frontline drug for treatment of acute promyelocytic leukemia and is in clinical trials for treatment of other malignancies, including multiple myeloma; however, efforts to expand clinical utility to solid tumors have been limited by toxicity. Nanoparticulate forms of As(2)O(3) encapsulated in 100-nm-scale, folate-targeted liposomes have been developed to lower systematic toxicity and provide a platform for targeting this agent. The resultant arsenic "nanobins" are stable under physiologic conditions but undergo triggered drug release when the pH is lowered to endosomal/lysosomal levels. Cellular uptake and antitumor efficacy of these arsenic liposomes have been evaluated in folate receptor (FR)-positive human nasopharyngeal (KB) and cervix (HeLa) cells, as well as FR-negative human breast (MCF-7) tumor cells through confocal microscopy, inductively coupled plasma mass spectroscopy, and cytotoxicity studies. Uptake of folate-targeted liposomal arsenic by KB cells was three to six times higher than that of free As(2)O(3) or nontargeted liposomal arsenic; the enhanced uptake occurs through folate-mediated endocytosis, leading to a 28-fold increase in cytotoxicity. In contrast, tumor cells with lower FR density on the surface (HeLa and MCF-7) showed much less uptake of the folate-targeted drug and lower efficacy. In cocultures of KB and MCF-7 cells, the folate-targeted arsenic liposomes were exclusively internalized by KB cells, showing high targeting specificity. Our studies further indicate that folate-targeted delivery of As(2)O(3) with coencapsulated nickel(II) ions (as a nontoxic adjuvant) potentiates the As(2)O(3) efficacy in relatively insensitive solid tumor-derived cells and holds the promise of improving drug therapeutic index.

PMID: 19567824 [PubMed - indexed for MEDLINE]

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In vitro and In vivo studies of local arterial gene delivery and transfection using lipopolyplexes-embedded stents.

J Biomed Mater Res A. 2010 Apr;93(1):325-36

Authors: Brito LA, Chandrasekhar S, Little SR, Amiji MM

Gene-eluting stents can have profound impact in the treatment of coronary restenosis, especially when the encoded protein can re-endothelialize the arterial lumen. In this study, we have examined gene delivery in vitro and in vivo using poly(beta-amino ester) (PbAE) precondensed plasmid DNA-containing cationic liposomes or lipopolyplexes (LPP) immobilized on stainless steel meshes and stents using gelatin coatings. In vitro studies using LPP-immobilized on 50 mm round meshes using type A and B gelatin coatings showed that LPP were efficiently internalized in human aortic smooth muscle cells (SMC) over time, leading to green fluorescent protein (GFP) expression. Type B gelatin coating was found to be more effective in intracellular delivery and transgene expression efficiency and, as such, was used for stent coating. In vivo studies, carried out in iliac artery restenosis model in New Zealand white rabbits, also showed GFP expression in arterial tissues after 24 h of implantation. Based on these encouraging preliminary results, LPP-based formulations can serve as a safe and effective nonviral gene delivery system for effective treatment of coronary restenosis.

PMID: 19569206 [PubMed - in process]

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Vesicular carriers for dermal drug delivery.

Expert Opin Drug Deliv. 2009 Aug;6(8):813-25

Authors: Sinico C, Fadda AM

The skin can offer several advantages as a route of drug administration although its barrier nature makes it difficult for most drugs to penetrate into and permeate through it. During the past decades there has been a lot of interest in lipid vesicles as a tool to improve drug topical delivery. Vesicular systems such as liposomes, niosomes, ethosomes and elastic, deformable vesicles provide an alternative for improved skin drug delivery. The function of vesicles as topical delivery systems is controversial with variable effects being reported in relation to the type of vesicles and their composition. In fact, vesicles can act as drug carriers controlling active release; they can provide a localized depot in the skin for dermally active compounds and enhance transdermal drug delivery. A wide variety of lipids and surfactants can be used to prepare vesicles, which are commonly composed of phospholipids (liposomes) or non-ionic surfactants (niosomes). Vesicle composition and preparation method influence their physicochemical properties (size, charge, lamellarity, thermodynamic state, deformability) and therefore their efficacy as drug delivery systems. A review of vesicle value in localizing drugs within the skin at the site of action will be provided with emphasis on their potential mechanism of action.

PMID: 19569979 [PubMed - indexed for MEDLINE]

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Effect of polyethyleneglycol spacer on the binding properties of nuclear localization signal-modified liposomes to isolated nucleus.

Biol Pharm Bull. 2009 Jul;32(7):1303-6

Authors: Kurihara D, Akita H, Kudo A, Masuda T, Futaki S, Harashima H

The nuclear delivery process is a crucial barrier to successful gene delivery, especially in non-dividing cells. We previously proposed a novel strategy for the nuclear delivery of plasmid DNA (pDNA), in which the pDNA is encapsulated in lipid bilayers that had been modified with nucleus-targeting signals, including nuclear localizing signals derived from SV40 (NLS) or sugar units. In the present study, we report on an investigation of the effect of the topology of the liposome-modified NLS on its ability to bind to the isolated nucleus. NLS was directly attached to a liposome (NLS-Lip) by incorporating stearylated NLS (STR-NSL), or by modification with a polyethyleneglycol (PEG) spacer (NLS-PEG-Lip). NLS-unmodified liposomes (PEG-Lip) were used as a control. The liposomes, after labeling with 7-nitrobenz-2-oxa-1,3-diazole (NBD), were incubated with a cell homogenate derived from JAWS II cells, followed by isolation of the nuclear fraction by centrifugation. The PEG-Lip preparation showed negligible binding to the nucleus. In contrast, the binding of NLS-Lips to the nucleus gradually increased in a STR-NLS density-dependent manner. Interestingly, the binding of NLS-PEG-Lips to the nucleus is highly effective even at low density, suggesting that the presence of the PEG spacer is an important factor in improving the binding activity of NLS-modified liposomes to the nucleus. This information will be useful for the design of nucleus-targeting carriers.

PMID: 19571404 [PubMed - indexed for MEDLINE]

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Protein-based nanomedicine platforms for drug delivery.

Small. 2009 Aug 3;5(15):1706-21

Authors: Maham A, Tang Z, Wu H, Wang J, Lin Y

Protein-based nanomedicine platforms for drug delivery comprise naturally self-assembled protein subunits of the same protein or a combination of proteins making up a complete system. They are ideal for drug-delivery platforms due to their biocompatibility and biodegradability coupled with low toxicity. A variety of proteins have been used and characterized for drug-delivery systems, including the ferritin/apoferritin protein cage, plant-derived viral capsids, the small Heat shock protein (sHsp) cage, albumin, soy and whey protein, collagen, and gelatin. There are many different types and shapes that have been prepared to deliver drug molecules using protein-based platforms, including various protein cages, microspheres, nanoparticles, hydrogels, films, minirods, and minipellets. The protein cage is the most newly developed biomaterial for drug delivery and therapeutic applications. The uniform size, multifunctionality, and biodegradability push it to the frontier of drug delivery. In this Review, the recent strategic development of drug delivery is discussed with emphasis on polymer-based, especially protein-based, nanomedicine platforms for drug delivery. The advantages and disadvantages are also discussed for each type of protein-based drug-delivery system.

PMID: 19572330 [PubMed - indexed for MEDLINE]

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A synthetic peptide mediated active targeting of cisplatin liposomes to Tie2 expressing cells.

J Control Release. 2009 Nov 3;139(3):174-81

Authors: Mai J, Song S, Rui M, Liu D, Ding Q, Peng J, Xu Y

Tie2 receptor is a receptor tyrosine kinase that plays important roles in vascular angiogenesis, and also highly expressed by a number of cancer cells. In this study, we reported an active targeting liposome system directed by a novel peptide ligand PH1 that can improve drug efficacies specifically to Tie2 expressing cells. The PH1 peptide (TMGFTAPRFPHY) was selected by phage display library screening combined with surface plasmon resonance binding assays. It was covalently conjugated to the distal end of DSPE-PEG(2000)-Maleimide lipid and loaded onto liposome membranes as the targeting ligand. These PH1-PEG-liposomes containing the anticancer drug cisplatin were showed to bind tightly to Tie2 positive cells, mediate active endocytosis of the drug containing liposomes, and result in much higher cell specific cytoxicities than mPEG coated liposomes. They can be used not only to target vascular endothelial cells for anti-angiogenesis effects, but also to improve drug delivery and release in Tie2 expressing cancer cells. Such liposome formulation may be developed into a very useful agent for metronomic chemotherapy.

PMID: 19576253 [PubMed - indexed for MEDLINE]

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Development of a new topical system: drug-in-cyclodextrin-in-deformable liposome.

Int J Pharm. 2009 Oct 1;380(1-2):174-80

Authors: Gillet A, Grammenos A, Compère P, Evrard B, Piel G

A new delivery system for cutaneous administration combining the advantages of cyclodextrin inclusion complexes and those of deformable liposomes was developed, leading to a new concept: drug-in-cyclodextrin-in-deformable liposomes. Deformable liposomes made of soybean phosphatidylcholine (PC) or dimyristoylphosphatidylcholine (DMPC) and sodium deoxycholate as edge activator were compared to classical non-deformable liposomes. Liposomes were prepared by the film evaporation method. Betamethasone, chosen as the model drug, was encapsulated in the aqueous cavity of liposomes by the use of cyclodextrins. Cyclodextrins allow an increase in the aqueous solubility of betamethasone and thus, the encapsulation efficiency in liposome vesicles. Liposome size, deformability and encapsulation efficiency were calculated. The best results were obtained with deformable liposomes made of PC in comparison with DMPC. The stability of PC vesicles was evaluated by measuring the leakage of encapsulated calcein on the one hand and the leakage of encapsulated betamethasone on the other hand. In vitro diffusion studies were carried out on Franz type diffusion cells through polycarbonate membranes. In comparison with non-deformable liposomes, these new vesicles showed improved encapsulation efficiency, good stability and higher in vitro diffusion percentages of encapsulated drug. They are therefore promising for future use in ex vivo and in vivo experiments.

PMID: 19576972 [PubMed - indexed for MEDLINE]

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Engineered chylomicron mimicking carrier emulsome for lymph targeted oral delivery of methotrexate.

Int J Pharm. 2009 Oct 1;380(1-2):181-8

Authors: Paliwal R, Paliwal SR, Mishra N, Mehta A, Vyas SP

The aim of the present study was to develop chylomicron mimicking carrier emulsome for oral lymphatic delivery of methotrexate (MTX), an anticancer drug. The compritol 888 ATO (CA) was used as lipid core and soya lecithin (PC) as stabilizer. The optimized emulsome (1:1.2 mole ratio of CA:PC) showed mean particle size of 160.3+/-10.2 nm and with 72.8+/-6.5% drug entrapment efficiency. The differential scanning calorimetric studies revealed a depression in endothermic onset for MTX loaded emulsome. The rapid burst release of the drug was observed in simulated gastric fluid (SGF pH 1.2) with significant increase in particle size of emulsome. However in simulated intestinal fluid (SIF, pH 7.4) a slow and consistent release of the drug was obtained over period of 24 h. Storage stability studies were performed at different temperatures (4+/-1 and 25+/-1 degrees C) for 3 months which suggested that EML remain more stable when stored at refrigerated condition. The in vivo studies were carried out on albino rats and response was estimated collecting blood and lymph both. The pharmacokinetic parameters C(max), t(max) and AUC(0-->12h) after duodenal administration of optimized emulsomal formulation and plain MTX solution were 7.1 and 2.4 microg/mL, 4 and 1 h, 40.45 and 7.2 h microg/mL respectively. The relative bioavailability of MTX was enhanced nearly 5.7 times with optimized EML formulation when compared to plain MTX solution with higher uptake and longer residence time of MTX molecules in lymphatics. Thus, emulsome could be used as lymphotropic carrier for delivery of bioactive(s) and hence for bioavailability enhancement.

PMID: 19576973 [PubMed - indexed for MEDLINE]