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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]
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