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Development of a bifunctional immunoliposome system for combined drug delivery and imaging in vivo.

Biomaterials. 2010 May;31(14):4139-45

Authors: Feng B, Tomizawa K, Michiue H, Han XJ, Miyatake S, Matsui H

The diverse characteristics of immunoliposomes provide advantages for utilization in drug delivery systems. In this study, we fused the antibody affinity motif of protein A (ZZ) with Gaussia luciferase (GLase). The fused protein conjugated with an anti-epidermal growth factor receptor (EGFR) monoclonal antibody (GLase-ZZ-His-mAb) was effectively delivered into glioma cells expressing an activated EGFR mutant (EGFRvIII) and the bioluminescence was visualized in the cells. Immunoliposomes were further constructed with DSPE-PEG-MAL for covalent GLase-ZZ-His-mAb conjugation. A fluorescence dye (HPTS) encapsulated in immunoliposomes conjugated with GLase-ZZ-His-mAb was effectively delivered into EGFRvIII-expressing glioma cells. In a murine xenograft model of glioma, moreover, specific targeting of the immunoliposomes was visualized in the tumor. This new bifunctional immunoliposome system has the potential for drug delivery and imaging in vivo.

PMID: 20149431 [PubMed - indexed for MEDLINE]

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Canine spontaneous glioma: A translational model system for convection-enhanced delivery.

Neuro Oncol. 2010 May 20;

Authors: Dickinson PJ, Lecouteur RA, Higgins RJ, Bringas JR, Larson RF, Yamashita Y, Krauze MT, Forsayeth J, Noble CO, Drummond DC, Kirpotin DB, Park JW, Berger MS, Bankiewicz KS

Canine spontaneous intracranial tumors bear striking similarities to their human tumor counterparts and have the potential to provide a large animal model system for more realistic validation of novel therapies typically developed in small rodent models. We used spontaneously occurring canine gliomas to investigate the use of convection-enhanced delivery (CED) of liposomal nanoparticles, containing topoisomerase inhibitor CPT-11. To facilitate visualization of intratumoral infusions by real-time magnetic resonance imaging (MRI), we included identically formulated liposomes loaded with Gadoteridol. Real-time MRI defined distribution of infusate within both tumor and normal brain tissues. The most important limiting factor for volume of distribution within tumor tissue was the leakage of infusate into ventricular or subarachnoid spaces. Decreased tumor volume, tumor necrosis, and modulation of tumor phenotype correlated with volume of distribution of infusate (Vd), infusion location, and leakage as determined by real-time MRI and histopathology. This study demonstrates the potential for canine spontaneous gliomas as a model system for the validation and development of novel therapeutic strategies for human brain tumors. Data obtained from infusions monitored in real time in a large, spontaneous tumor may provide information, allowing more accurate prediction and optimization of infusion parameters. Variability in Vd between tumors strongly suggests that real-time imaging should be an essential component of CED therapeutic trials to allow minimization of inappropriate infusions and accurate assessment of clinical outcomes.

PMID: 20488958 [PubMed - as supplied by publisher]

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Design of a dual-ligand system using a specific ligand and cell penetrating peptide, resulting in a synergistic effect on selectivity and cellular uptake.

Int J Pharm. 2010 May 8;

Authors: Takara K, Hatakeyama H, Ohga N, Hida K, Harashima H

In this study, a dual-ligand liposomal system comprised of a specific ligand and a cell penetrating peptide (CPP) is described to enhance selectivity and cellular uptake. Dual-ligand PEGylated liposomes were prepared by modifying the end of the PEG with an NGR motif peptide, followed by a surface coating of the liposomes with stearylated oligoarginine (STR-RX). The NGR motif recognizes CD13, a marker protein located on tumor endothelial cells. A suitable number of RX units was determined to be R4, since it can be masked by the PEG aqueous layer. Although no enhanced cellular uptake was observed when a single modification of PEGylated liposomes with either NGR- or STR-R4 was used, the dual-modification with NGR and STR-R4 stimulated uptake of PEGylated liposomes by CD13 positive cells, and this uptake was superior to that obtained by PEG-unmodified liposomes modified with STR-R4. The dual-ligand system shows a synergistic effect on cellular uptake. Collectively, the dual-ligand system promises to be useful in the development efficient and specific drug delivery systems.

PMID: 20457236 [PubMed - as supplied by publisher]

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Applications of novel drug delivery system for herbal formulations.

Fitoterapia. 2010 May 12;

Authors: Ajazuddin , Saraf S

Over the past several years, great advances have been made on development of novel drug delivery systems (NDDS) for plant actives and extracts. The variety of novel herbal formulations like polymeric nanoparticles, nanocapsules, liposomes, phytosomes, nanoemulsions, microsphere, transferosomes, and ethosomes have been reported using bioactive and plant extracts. The novel formulations reported to have remarkable advantages over conventional formulations of plant actives and extracts which includes enhancement of solubility, bioavailability, protection from toxicity, enhancement of pharmacological activity, enhancement of stability, improved tissue macrophages distribution, sustained delivery, protection from physical and chemical degradation. The present review highlights the current status of the development of novel herbal formulations and summarizes their method of preparation, type of active ingredients, size, entrapment efficiency, route of administration, biological activity and applications of novel formulations.

PMID: 20471457 [PubMed - as supplied by publisher]

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Peptide-mediated liposomal drug delivery system targeting tumor blood vessels in anticancer therapy.

J Oncol. 2010;2010:723798

Authors: Wu HC, Chang DK

Solid tumors are known to recruit new blood vessels to support their growth. Therefore, unique molecules expressed on tumor endothelial cells can function as targets for the antiangiogenic therapy of cancer. Current efforts are focusing on developing therapeutic agents capable of specifically targeting cancer cells and tumor-associated microenvironments including tumor blood vessels. These therapies hold the promise of high efficacy and low toxicity. One recognized strategy for improving the therapeutic effectiveness of conventional chemotherapeutics is to encapsulate anticancer drugs into targeting liposomes that bind to the cell surface receptors expressed on tumor-associated endothelial cells. These anti-angiogenic drug delivery systems could be used to target both tumor blood vessels as well as the tumor cells, themselves. This article reviews the mechanisms and advantages of various present and potential methods using peptide-conjugated liposomes to specifically destroy tumor blood vessels in anticancer therapy.

PMID: 20454584 [PubMed - in process]

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Development and characterization of minoxidil-loaded liposomal system for delivery to pilosebaceous units.

J Liposome Res. 2010 Jun;20(2):105-14

Authors: Jain B, Singh B, Katare OP, Vyas SP

The current study aimed to deliver minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide; MXD), a potent hypertrichotic agent, into the pilosebaceous units, exploring the potential of the liposomal system. MXD-loaded liposomes of different compositions were prepared by a thin-film hydration technique and subsequently characterized for various vesicle-specific attributes (i.e., size, shape, lamellarity, and entrapment efficiency). Comparative analysis among these compositions was conducted with reference to their vesicle-specific parameters, drug deposition, and drug-delivery mechanism toward pilosebaceous units. The latter may bring about a distinct change in MXD therapy for various ailments related to pilosebaceous units, such as alopecia. The in vitro drug release, ex vivo skin permeation, and drug-retention behavior of the prepared formulation were evaluated by employing rat skin (normal as well as pilosebaceous free) and semipermeable membrane. The results revealed that the neutral liposomes (mean vesicle size, 3.83 +/- 0.18 microm) showed maximum drug deposition in the pilosebaceous units among all the other tested formulations. A quantitative estimation of pilosebaceous delivery revealed that the concentration of MXD in each pilosebaceous unit decreased in the following order: neutral liposomal formulation (5.8 x 10(3) to 7.25 x 10(3) microg) > positively charged liposomal formulation (4.7 x 10(3) to 5.87 x 10(3) microg) > negatively charged liposomal formulation (4.2 x 10(3) to 5.25 x 10(3) microg) > nonliposomal formulation (1.6 x 10(3) to 2.0 x 10(3) microg). Stability studies construed the need to store the liposomal formulation at lower temperatures. The results of the current work indicate that the neutral liposomes can deliver the drug molecules into pilosebaceous units more effectively than the other studied formulations.

PMID: 19698000 [PubMed - in process]

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Methods, potentials, and limitations of gene delivery to regenerate central nervous system cells.

Biologics. 2009;3:245-56

Authors: Kumar A, Singh TD, Singh SK, Prakash S

This review evaluates methods, success and limitations of transgenes delivery in central nervous system (CNS). Both viral and nonviral (such as liposome mediated) methods, expression and stability of transgenes have been discussed. The controlled expression and delivery techniques of transgene at the injured or diseased sites have also been discussed. Mifepristone (RU486) and tetracycline-based switch system for controlled expression could be a very useful tool for clinical purposes. Here we emphasized the importance and consequences of viral- and nonviral-mediated transgenes transfer and therapeutic ability along with advantages of controlled expressions.

PMID: 19707413 [PubMed]

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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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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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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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Proniosomal transdermal therapeutic system of losartan potassium: development and pharmacokinetic evaluation.

J Drug Target. 2009 Jul;17(6):442-9

Authors: Thakur R, Anwer MK, Shams MS, Ali A, Khar RK, Shakeel F, Taha EI

The purpose of the current study was to investigate the feasibility of proniosomes as transdermal drug delivery system for losartan potassium. Different preparations of proniosomes were fabricated using different nonionic surfactants, such as Span 20, Span 40, Span 60, Span 80, Tween 20, Tween 40, and Tween 80. Different formulae were prepared and coded as PNG-1 (proniosomal gel-1) to PNG-7. The best in vitro skin permeation profile was obtained with proniosomal formulation PNG-2 in 24 h. The permeability parameters such as flux, permeability coefficient, and enhancement ratio were significant for PNG-2 compared with other formulations (P < 0.05). This optimized PNG-2 was fabricated in the form of transdermal patch using HPMC gel as a suitable base. Proniosomal transdermal therapeutic system (PNP-H) was found to be the optimized one as it gave better release of drug and better permeation in a steady-state manner over a desired period of time, that is, 24 h through rat skin. In vivo pharmacokinetic study of PNP-H showed a significant increase in bioavailability (1.93 times) compared with oral formulation of losartan potassium. The formulation appeared to be stable when stored at room temperature (30 +/- 2 degrees C) and at refrigeration temperature (4 +/- 2 degrees C) for 45 days.

PMID: 19527115 [PubMed - indexed for MEDLINE]