Liposome Technology blog

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Delivery of PAR-4 plasmid in vivo via nanoliposomes sensitizes colon tumor cells subcutaneously implanted into nude mice to 5-FU.

Cancer Biol Ther. 2009 Oct;8(19):1831-7

Authors: Kline CL, Shanmugavelandy SS, Kester M, Irby RB

The prostate apoptosis response protein 4 (Par-4), a tumor suppressor, has been shown to induce apoptosis in cancer cells. While reduced Par-4 expression has been linked to survival of some cancers, its involvement in colon cancer has not been well documented. To explore the feasibility of increasing Par-4 in colon cancer to induce apoptosis, the human colon cancer cell line, HT29, was transfected to overexpress Par-4. In these cells, overexpressed Par-4 led to increased apoptosis in the presence of 5-fluorouracil. Subsequently, PAR-4 cDNA was packaged in nanoliposomal particles. Treating cells with the Par-4 nanoliposomes also increased susceptibility to 5-FU. These nanoliposomes were used to deliver Par-4 plasmid to tumors growing in nude mice from wild type HT29 cells. Results showed that nanoliposomes effectively delivered plasmid DNA to tumors in vivo. Again, tumors in mice treated with the Par-4 nanoliposomes were more susceptible to 5-FU treatment. This suggests that upregulation of Par-4 expression is a potentially useful mechanism to enhance the current chemotherapeutic regimen for colon cancer. Packaging Par-4 cDNA in nanoliposomal particles is a promising delivery method to increase response to chemotherapy.

PMID: 19729995 [PubMed - indexed for MEDLINE]

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Evaluation of particulate acellular vaccines against Brucella ovis infection in rams.

Vaccine. 2010 Apr 9;28(17):3038-46

Authors: Da Costa Martins R, Irache JM, Blasco JM, Muñoz MP, Marín CM, Jesús Grilló M, Jesús De Miguel M, Barberán M, Gamazo C

The attenuated Brucella melitensis Rev 1 vaccine, used against brucellosis infection, interferes with serological diagnosis tests, may induce abortions in pregnant animals, and may infect humans. In order to overcome these drawbacks, we developed acellular vaccines based on a Brucella ovis antigenic complex (HS) containing outer membrane proteins and R-LPS entrapped in poly(anhydride) conventional and mannosylated nanoparticles (NP-HS and MAN-NP-HS) or in poly(epsilon-caprolactone) microparticles (HS-PEC) as antigen delivery systems and immunoadjuvants. Brucellosis free rams were vaccinated subcutaneously with a single dose of particles containing 3mg of HS, and challenged 6 months thereafter. Protection was evaluated by clinical, bacteriological and serological examinations, in comparison with non-vaccinated control rams. HS-PEC vaccine induced protection (7 out of 13 animals were infected) equivalent to that induced by the reference Rev 1 vaccine (8/14). In contrast, animals immunized with NP-HS were not protected, showing similar results to that obtained in the control unvaccinated rams. Furthermore HS-PEC vaccine did not interfere against B. melitensis serodiagnostic tests. In summary, HS-PEC microparticles could be used as a safe and effective vaccine against brucellosis in rams.

PMID: 19887131 [PubMed - indexed for MEDLINE]

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Non-invasive monitoring of intra-tumor drug concentration and therapeutic response using optical spectroscopy.

J Control Release. 2010 Mar 19;142(3):457-64

Authors: Palmer GM, Boruta RJ, Viglianti BL, Lan L, Spasojevic I, Dewhirst MW

Optical spectroscopy was used to monitor changes in tumor physiology with therapy, and its influence on drug delivery and treatment efficacy for hyperthermia treatment combined with free doxorubicin or a low-temperature sensitive liposomal formulation. Monte Carlo-based modeling techniques were used to characterize the intrinsic absorption, scattering, and fluorescence properties of tissue. Fluorescence assessment of drug concentration was validated against HPLC and found to be significantly linearly correlated (r=0.88). Cluster analysis on the physiologic data obtained by optical spectroscopy revealed two physiologic phenotypes prior to treatment. One of these was relatively hypoxic, with relatively low total hemoglobin content. This hypoxic group was found to have a significantly shorter time to reach 3 times pre-treatment volume, indicating a more treatment resistant phenotype (p=0.003). Influence of tumor physiology was assessed in more detail for the liposomal doxorubicin+hyperthermia group, which demonstrated a highly significant correlation between pre-treatment hemoglobin saturation and tumor growth delay, and also between post-hyperthermia total hemoglobin content and tumor drug delivery. Finally, it was found that the doxorubicin concentration, measured in vivo using fluorescence techniques significantly predicted for chemoresponse (hazard ratio: 0.34, p=0.0007). The ability to characterize drug delivery and tumor physiology in vivo makes this a potentially useful tool for evaluating the efficacy of targeted delivery systems in preclinical studies, and may be translatable for monitoring and predicting individual treatment responses in the clinic.

PMID: 19896999 [PubMed - indexed for MEDLINE]

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Development of nanoparticles for antimicrobial drug delivery.

Curr Med Chem. 2010;17(6):585-94

Authors: Zhang L, Pornpattananangku D, Hu CM, Huang CM

This review focuses on the development of nanoparticle systems for antimicrobial drug delivery. Numerous antimicrobial drugs have been prescribed to kill or inhibit the growth of microbes such as bacteria, fungi and viruses. Even though the therapeutic efficacy of these drugs has been well established, inefficient delivery could result in inadequate therapeutic index and local and systemic side effects including cutaneous irritation, peeling, scaling and gut flora reduction. Nanostructured biomaterials, nanoparticles in particular, have unique physicochemical properties such as ultra small and controllable size, large surface area to mass ratio, high reactivity, and functionalizable structure. These properties can be applied to facilitate the administration of antimicrobial drugs, thereby overcoming some of the limitations in traditional antimicrobial therapeutics. In recent years, encapsulation of antimicrobial drugs in nanoparticle systems has emerged as an innovative and promising alternative that enhances therapeutic effectiveness and minimizes undesirable side effects of the drugs. Here the current progress and challenges in synthesizing nanoparticle platforms for delivering various antimicrobial drugs are reviewed. We also call attention to the need to unite the shared interest between nanoengineers and microbiologists in developing nanotechnology for the treatment of microbial diseases.

PMID: 20015030 [PubMed - indexed for MEDLINE]

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RON receptor tyrosine kinase as a target for delivery of chemodrugs by antibody directed pathway for cancer cell cytotoxicity.

Mol Pharm. 2010 Apr 5;7(2):386-97

Authors: Guin S, Yao HP, Wang MH

Overexpression of the RON receptor tyrosine kinase exists in various cancers and contributes to malignant progression. To validate RON as a targeting moiety for delivery of chemoagents for enhanced tumor cytotoxicity, immunoliposomes (IL) loaded with doxorubicin (Dox) were formulated followed by postinsertion of monoclonal antibodies Zt/g4, Zt/c1, or their Fab fragments specific to the RON extracellular domains. Flow cytometry analysis showed that Zt/g4 or Zt/c1-IL binds to cancer cells and causes RON internalization as evident in confocal analysis of intracellular fluorescence intensity. The antibody-directed IL uptake by cancer cells is in both dose and time-dependent manners. Studies of cytotoxicity of individual IL in vitro against colon or breast cancer cell lines revealed that Zt/g4 directed Dox-IL displayed increased cytotoxic activities with a significant reduction of IC(50) values. An average of 8-fold increases in cytotoxic efficiency was achieved among four cell lines tested. Moreover, Zt/g4 directed Dox-IL also displayed the effective killing of cancer cells that are insensitive to pegylated liposomal doxorubicin. The effect of Zt/c1-Dox-IL was not as strong as Zt/g4-Dox-IL, and only moderate activities were observed. IL coupled with the Fab fragments of Zt/g4 or Zt/c1 show moderate activities against cancer cells. The ineffectiveness seemed to be related to the weak activities of the Fab fragments in the induction of RON internalization, which resulted in reduced drug uptakes. We conclude that anti-RON antibody-directed drug delivery is effective for increased uptake of cytotoxic drugs. Antibody-based RON targeting could be developed into a potential therapeutic for treatment of malignant cancers.

PMID: 20039696 [PubMed - indexed for MEDLINE]

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In vitro and in vivo evaluation of proniosomes containing celecoxib for oral administration.

AAPS PharmSciTech. 2010 Mar;11(1):85-9

Authors: Nasr M

The objectives of this research were to prepare celecoxib proniosomes and evaluate the influence of proniosomal formulation on the oral bioavailability of the drug in human volunteers. A new proniosomal delivery system for a poorly water-soluble drug such as celecoxib was developed and subjected to in vitro and in vivo studies. Proniosomes were prepared by sequential spraying method, which consisted of cholesterol, span 60, and dicetyl phosphate in a molar ratio of 1:1: 0.1, respectively. The average entrapment percent of celecoxib proniosome-derived niosomes was about 95%. The prepared proniosomes showed marked enhancement in the dissolution of celecoxib as compared to pure drug powder. The bioavailability of 200 mg single dose of both celecoxib proniosomal formulation and a conventional marketed celecoxib capsule was studied in human volunteers. The obtained results show that the proniosomal formulation significantly improved the extent of celecoxib absorption than conventional capsule. The mean relative bioavailability of the proniosomal formulation to the conventional capsule was 172.06 +/- 0.14%. The mean T (max) for celecoxib was prolonged when given as proniosomal capsule. There was no significant difference between the values of K (el) and t (1/2) for both celecoxib preparations. In conclusion, the proniosomal oral delivery system of celecoxib with improved bioavailability was established.

PMID: 20058106 [PubMed - indexed for MEDLINE]

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Overcoming cisplatin resistance of ovarian cancer cells by targeted liposomes in vitro.

Int J Pharm. 2010 Apr 15;389(1-2):10-7

Authors: Krieger ML, Eckstein N, Schneider V, Koch M, Royer HD, Jaehde U, Bendas G

The clinical application of cisplatin to treat solid tumours is often limited by the development of tumour cell resistance against this cytostatic agent. Although liposomal carriers of cisplatin are currently in clinical development, approaches to functionally overcome cisplatin resistance by liposomes have hardly been reported. We prepared PEGylated cisplatin-containing liposomes with diameters of about 110 nm and targetability to transferrin receptors (TfR) to correlate cisplatin cell uptake with cytotoxicity in sensitive and cisplatin resistant ovarian cancer cells A2780 compared to the free drug. Whereas the cell entry of free cisplatin was reduced by factor 4 after 24h in resistant cells, liposomal uptake was similar in both cell lines and not affected by resistance. Cytotoxicity was clearly related to intracellular platinum levels, which were even higher for liposomal vs. free cisplatin in the resistant cells after 24, 48, and 72 h and slightly lower in the sensitive cells. However, TfR targeting was of less impact on activity in comparison to non-targeted liposomes. Detection of cellular ATP levels within 24h allowed postulations on the intracellular fate of the liposomes. Altogether, this study strongly supports approaches to overcome cisplatin resistance by a liposomal application of the drug.

PMID: 20060458 [PubMed - indexed for MEDLINE]

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Liposomal simvastatin attenuates neointimal hyperplasia in rats.

AAPS J. 2010 Jun;12(2):181-7

Authors: Afergan E, Ben David M, Epstein H, Koroukhov N, Gilhar D, Rohekar K, Danenberg HD, Golomb G

Monocytes, macrophages, and inflammation play a key role in the process of neointimal proliferation and restenosis. The present study evaluated whether systemic and transient depletion of monocytes could be obtained by a single intravenous (IV) injection of simvastatin liposomes, for the inhibition of neointima formation. Balloon-injured carotid artery rats (n = 30) were randomly assigned to treatment groups of free simvastatin, simvastatin in liposomes (3 mg/kg), and saline (control). Stenosis and neointima to media ratio (N/M) were determined 14 days following single IV injection at the time of injury by morphometric analysis. Depletion of circulating monocytes was determined by flow cytometry analyzes of blood specimens. Inhibition of RAW264.7, J774, and THP-1 proliferation by simvastatin-loaded liposomes and free simvastatin was determined by the 3-(4, 5-dimethylthiazolyl-2)-2, 5- diphenyltetrazolium bromide assay. Simvastatin liposomes were successfully formulated and were found to be 1.5-2 times more potent than the free drug in suppressing the proliferation of monocytes/macrophages in cell cultures of RAW 264.7, J774, and THP-1. IV injection of liposomal simvastatin to carotid-injured rats (3 mg/kg, n = 4) resulted in a transient depletion of circulating monocytes, significantly more prolonged than that observed following treatment with free simvastatin. Administration to balloon-injured rats suppressed neointimal growth. N/M at 14 days was 1.56 +/- 0.16 and 0.90 +/- 0.12, control and simvastatin liposomes, respectively. One single systemic administration of liposomal simvastatin at the time of injury significantly suppresses neointimal formation in the rat model of restenosis, mediated via a partial and transient depletion of circulating monocytes.

PMID: 20143196 [PubMed - indexed for MEDLINE]

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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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Lipoplexes formulation and optimisation: in vitro transfection studies reveal no correlation with in vivo vaccination studies.

Curr Drug Deliv. 2010 Apr;7(2):175-87

Authors: McNeil SE, Vangala A, Bramwell VW, Hanson PJ, Perrie Y

The aim of these studies was to compare the effect of liposome composition on physico-chemical characteristics and transfection efficacy of cationic liposomes both in vitro and in vivo. Comparison between 4 popularly used cationic lipids, showed 3b-N-(dimethylaminoethyl)carbamate (DC-Chol) to promote the highest transfect levels in cells in vitro with levels being at least 6 times higher than those of 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA). 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and dimethyldioctadecylammonium (DDA) and approximately twice as efficient as dipalmitoyl-trimethylammonium-propane (DPTAP). To establish the role of the helper lipid, DC-Chol liposomes were formulated in combination with either 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE) or cholesterol (Chol) (1:1 molar ratio) with and without the addition of phosphatidyl choline. The choice of helper lipid incorporated within the bilayer was found to influence the formation of complexes, their resultant structure and their transfection efficiency in vitro, with SUV-DNA complexes containing optimum levels of DOPE giving higher transfection than those containing cholesterol. The inclusion of PC within the formulation also reduced transfection efficiency in vitro. However, when administered in vivo, SUV-DNA complexes composed of PC:Chol:DC-Chol at a molar ratio of 16:8:4 micromole/ml were the most effective at inducing splenocyte proliferation upon exposure to antigen in comparison to control spleens. These results demonstrate that there is no in vitro/in vivo correlation between the transfection efficacy of these liposome formulations and in vitro transfection in the above cell model cannot be taken as a reliable indicator for in vivo efficacy of DNA vaccines.

PMID: 20158478 [PubMed - indexed for MEDLINE]

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In vivo targeting of B-cell lymphoma with glycan ligands of CD22.

Blood. 2010 Jun 10;115(23):4778-86

Authors: Chen WC, Completo GC, Sigal DS, Crocker PR, Saven A, Paulson JC

Antibody-mediated cell depletion therapy has proven to provide significant clinical benefit in treatment of lymphomas and leukemias, driving the development of improved therapies with novel mechanisms of cell killing. A current clinical target for B-cell lymphoma is CD22, a B-cell-specific member of the sialic acid binding Ig-like lectin (siglec) family that recognizes alpha2-6-linked sialylated glycans as ligands. Here, we describe a novel approach for targeting B lymphoma cells with doxorubicin-loaded liposomal nanoparticles displaying high-affinity glycan ligands of CD22. The targeted liposomes are actively bound and endocytosed by CD22 on B cells, and significantly extend life in a xenograft model of human B-cell lymphoma. Moreover, they bind and kill malignant B cells from peripheral blood samples obtained from patients with hairy cell leukemia, marginal zone lymphoma, and chronic lymphocytic leukemia. The results demonstrate the potential for using a carbohydrate recognition-based approach for efficiently targeting B cells in vivo that can offer improved treatment options for patients with B-cell malignancies.

PMID: 20181615 [PubMed - indexed for MEDLINE]

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Effects of application method on skin penetration of carboxyfluorescein incorporated in liposomes.

Chem Pharm Bull (Tokyo). 2010;58(3):429-31

Authors: Shimoyama Y, Fujii M, Kanda Y, Mizoguchi A, Oda H, Koizumi N, Watanabe Y

We investigated the skin penetration of liposomes under two different application conditions; occluded and large application amount (1 ml/cm(2)), and open and small application amount (10 mul/cm(2)). Liposomes containing fluorescence-labeled phospholipids or carboxyfluorescein (CF) were used. In application under occluded conditions, phospholipids showed no penetration, even in the stratum corneum (SC). CF penetration in the skin after application of liposome was no different that after application of CF solution. In contrast, phospholipids penetrated the skin, particularly the SC and hair follicles, under open conditions. CF in liposome showed enhanced penetration in the SC and epidermis, but not in the dermis. On observation of the drying process, CF recrystallized from solution, but this did not occur with CF incorporated into liposome. It is possible that crystallization of CF is prevented by encapsulation in liposome, or that penetration occurs more readily with liposome.

PMID: 20190458 [PubMed - indexed for MEDLINE]

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Intracellular trafficking, metabolism and toxicity of current gene carriers.

Curr Drug Metab. 2009 Oct;10(8):885-94

Authors: Kuo WT, Huang HY, Huang YY

Gene delivery remains to be a very challenging field to efficiently transport the therapeutic gene and to modulate proteins with the desired function at the target site. The physiochemical and biological barriers are the major hurdles that need to be considered, particularly when administered systematically, in order to optimize the therapeutic efficacy. Numerous modifications have been extensively investigated aiming to provide protection from the plasma degradation, enhancement of transfection, target specificity, and most importantly, minimizing the side effects such as cellular toxicity and immune response. This article provides a review with respect to the in vitro and in vivo toxicity, as well as cellular and physiological interactions with the gene delivery system composed from viral vectors, cationic lipids and polymers. Recent progress and development are also addressed, with promising results that may be further adopted for clinical use.

PMID: 20214583 [PubMed - indexed for MEDLINE]

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Passive and active drug targeting: drug delivery to tumors as an example.

Handb Exp Pharmacol. 2010;(197):3-53

Authors: Torchilin VP

The paradigm of using nanoparticulate pharmaceutical carriers has been well established over the past decade, both in pharmaceutical research and in the clinical setting. Drug carriers are expected to stay in the blood for long time, accumulate in pathological sites with affected and leaky vasculature (tumors, inflammations, and infarcted areas) via the enhanced permeability and retention (EPR) effect, and facilitate targeted delivery of specific ligand-modified drugs and drug carriers into poorly accessible areas. Among various approaches to specifically target drug-loaded carrier systems to required pathological sites in the body, two seem to be most advanced--passive (EPR effect-mediated) targeting, based on the longevity of the pharmaceutical carrier in the blood and its accumulation in pathological sites with compromised vasculature, and active targeting, based on the attachment of specific ligands to the surface of pharmaceutical carriers to recognize and bind pathological cells. Here, we will consider and discuss these two targeting approaches using tumor targeting as an example.

PMID: 20217525 [PubMed - indexed for MEDLINE]

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Nanoparticle technologies for cancer therapy.

Handb Exp Pharmacol. 2010;(197):55-86

Authors: Alexis F, Pridgen EM, Langer R, Farokhzad OC

Nanoparticles as drug delivery systems enable unique approaches for cancer treatment. Over the last two decades, a large number of nanoparticle delivery systems have been developed for cancer therapy, including organic and inorganic materials. Many liposomal, polymer-drug conjugates, and micellar formulations are part of the state of the art in the clinics, and an even greater number of nanoparticle platforms are currently in the preclinical stages of development. More recently developed nanoparticles are demonstrating the potential sophistication of these delivery systems by incorporating multifunctional capabilities and targeting strategies in an effort to increase the efficacy of these systems against the most difficult cancer challenges, including drug resistance and metastatic disease. In this chapter, we will review the available preclinical and clinical nanoparticle technology platforms and their impact for cancer therapy.

PMID: 20217526 [PubMed - indexed for MEDLINE]

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Carriers in the topical treatment of skin disease.

Handb Exp Pharmacol. 2010;(197):435-68

Authors: Korting HC, Schäfer-Korting M

Topical drug application is less prone to severe systemic side-effects than systemic application. Starting with the liposomes, various types of nanosized and microsized drug carriers have been developed to increase the notoriously low penetration of active agents into the skin, which limits not only the topical therapy of skin disease but also transdermal therapy. Today, liposome- and microsponge-based preparations are approved for dermatomycosis, acne and actinic keratosis. Under investigation are drug carriers such as lipid nanoparticles, polymeric particles, dendrimers, and dendritic-core multi-shell nanotransporters. According to the rapidly increasing research in this field, both in academia and industry, a breakthrough appears likely, once stability problems (nanoparticles) and safety concerns (dendrimers) are overcome. Technical approaches and results of in vitro, ex vivo and in vivo testing are described, taking into account pharmacokinetic, efficacy and safety aspects.

PMID: 20217539 [PubMed - indexed for MEDLINE]

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Antibody targeting of nanoparticles to tumor-specific receptors: immunoliposomes.

Methods Mol Biol. 2010;624:295-308

Authors: Rothdiener M, Beuttler J, Messerschmidt SK, Kontermann RE

Immunoliposomes generated by coupling of antibodies to the liposomal surface allow for an active tissue targeting, e.g., through binding to tumor cell-specific receptors. Instead of whole antibodies, single-chain Fv fragments (scFv), which represent the smallest part of an antibody containing the entire antigen-binding site, find increasing usage as targeting moiety. Here we provide protocols for the preparation of type II scFv immunoliposomes by the conventional coupling method as well as the post-insertion method. Furthermore protocols to analyze binding of these immunoliposomes to antigen-expressing cells as well as internalization through receptor-mediated endocytosis are included.

PMID: 20217604 [PubMed - indexed for MEDLINE]

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Cooperative nanoparticles for tumor detection and photothermally triggered drug delivery.

Adv Mater. 2010 Feb 23;22(8):880-5

Authors: Park JH, von Maltzahn G, Ong LL, Centrone A, Hatton TA, Ruoslahti E, Bhatia SN, Sailor MJ

PMID: 20217810 [PubMed - indexed for MEDLINE]

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Insight into the cellular uptake mechanism of a secondary amphipathic cell-penetrating peptide for siRNA delivery.

Biochemistry. 2010 Apr 27;49(16):3393-402

Authors: Konate K, Crombez L, Deshayes S, Decaffmeyer M, Thomas A, Brasseur R, Aldrian G, Heitz F, Divita G

Delivery of siRNA remains a major limitation to their clinical application, and several technologies have been proposed to improve their cellular uptake. We recently described a peptide-based nanoparticle system for efficient delivery of siRNA into primary cell lines: CADY. CADY is a secondary amphipathic peptide that forms stable complexes with siRNA and improves their cellular uptake independently of the endosomal pathway. In the present work, we have combined molecular modeling, spectroscopy, and membrane interaction approaches in order to gain further insight into CADY/siRNA particle mechanism of interaction with biological membrane. We demonstrate that CADY forms stable complexes with siRNA and binds phospholipids tightly, mainly through electrostatic interactions. Binding to siRNA or phospholipids triggers a conformational transition of CADY from an unfolded state to an alpha-helical structure, thereby stabilizing CADY/siRNA complexes and improving their interactions with cell membranes. Therefore, we propose that CADY cellular membrane interaction is driven by its structural polymorphism which enables stabilization of both electrostatic and hydrophobic contacts with surface membrane proteoglycan and phospholipids.

PMID: 20302329 [PubMed - indexed for MEDLINE]

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Designer lipids advance systemic siRNA delivery.

Mol Ther. 2010 Apr;18(4):669-70

Authors: Liu Y, Huang L

PMID: 20357780 [PubMed - indexed for MEDLINE]

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Quercetin in vesicular delivery systems: evaluation in combating arsenic-induced acute liver toxicity associated gene expression in rat model.

Chem Biol Interact. 2010 Jun 7;186(1):61-71

Authors: Ghosh D, Ghosh S, Sarkar S, Ghosh A, Das N, Das Saha K, Mandal AK

Arsenic, the environmental toxicant causes oxidative damage to liver and produces hepatic fibrosis. The theme of our study was to evaluate the therapeutic efficacy of liposomal and nanocapsulated herbal polyphenolic antioxidant quercetin (QC) in combating arsenic induced hepatic oxidative stress, fibrosis associated upregulation of its gene expression and plasma TGF beta (transforming growth factor beta) in rat model. A single dose of arsenic (sodium arsenite-NaAsO(2), 13 mg/kgb.wt) in oral route causes the generation of reactive oxygen species (ROS), arsenic accumulation in liver, hepatotoxicity and decrease in hepatic plasma membrane microviscosity and antioxidant enzyme levels in liver. Arsenic causes fibrosis associated elevation of its gene expression in liver, plasma TGF ss (from normal value 75.2+/-8.67 ng/ml to 196.2+/-12.07 ng/ml) and release of cytochrome c in cytoplasm. Among the two vesicular delivery systems formulated with QC, polylactide nanocapsules showed a promising result compared to liposomal delivery system in controlling arsenic induced alteration of those parameters. A single dose of 0.5 ml of nanocapsulated QC suspension (QC 2.71 mg/kg b.wt) when injected to rats 1h after arsenic administration orally protects liver from arsenic induced deterioration of antioxidant levels as well as oxidative stress associated gene expression of liver. Histopathological examination also confirmed the pathological improvement in liver. Nanocapsulated plant origin flavonoidal compound may be a potent formulation in combating arsenic induced upregulation of gene expression of liver fibrosis through a complete protection against oxidative attack in hepatic cells of rat liver.

PMID: 20371363 [PubMed - indexed for MEDLINE]

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Distamycins: strategies for possible enhancement of activity and specificity.

Mini Rev Med Chem. 2010 Mar;10(3):217-30

Authors: Cortesi R, Esposito E

The present review focused on the strategies aimed to possibly solve toxicity problems of distamycins. Distamycins are compounds characterized by an oligopeptidic pyrrolocarbamoyl frame ending with an amidino moiety. This class of compounds displays antiviral and antibiotic activity and shows interesting antiprotozoal activity related to the ability to reversibly bind to the minor groove of DNA with a high selectivity for TA-rich sequences. In consideration of their potential therapeutic properties, the synthesis of new distamycin derivatives and especially the development of controlled delivery strategies, could lead to important advantages in the clinical use of these molecules, possibly overcoming or mitigating the low solubility, specificity and toxicity problems associated with their use. To these aims an ensemble of the main synthetic distamycin derived compounds and of the potential drug delivery systems for distamycins described in literature is reviewed.

PMID: 20408803 [PubMed - indexed for MEDLINE]

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Sustained small interfering RNA delivery by mesoporous silicon particles.

Cancer Res. 2010 May 1;70(9):3687-96

Authors: Tanaka T, Mangala LS, Vivas-Mejia PE, Nieves-Alicea R, Mann AP, Mora E, Han HD, Shahzad MM, Liu X, Bhavane R, Gu J, Fakhoury JR, Chiappini C, Lu C, Matsuo K, Godin B, Stone RL, Nick AM, Lopez-Berestein G, Sood AK, Ferrari M

RNA interference (RNAi) is a powerful approach for silencing genes associated with a variety of pathologic conditions; however, in vivo RNAi delivery has remained a major challenge due to lack of safe, efficient, and sustained systemic delivery. Here, we report on a novel approach to overcome these limitations using a multistage vector composed of mesoporous silicon particles (stage 1 microparticles, S1MP) loaded with neutral nanoliposomes (dioleoyl phosphatidylcholine, DOPC) containing small interfering RNA (siRNA) targeted against the EphA2 oncoprotein, which is overexpressed in most cancers, including ovarian. Our delivery methods resulted in sustained EphA2 gene silencing for at least 3 weeks in two independent orthotopic mouse models of ovarian cancer following a single i.v. administration of S1MP loaded with EphA2-siRNA-DOPC. Furthermore, a single administration of S1MP loaded with-EphA2-siRNA-DOPC substantially reduced tumor burden, angiogenesis, and cell proliferation compared with a noncoding control siRNA alone (SKOV3ip1, 54%; HeyA8, 57%), with no significant changes in serum chemistries or in proinflammatory cytokines. In summary, we have provided the first in vivo therapeutic validation of a novel, multistage siRNA delivery system for sustained gene silencing with broad applicability to pathologies beyond ovarian neoplasms.

PMID: 20430760 [PubMed - indexed for MEDLINE]