A review of mechanistic insight and application of pH-sensitive liposomes in drug delivery (original) (raw)
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pH-Sensitive liposomes-principle and application in cancer therapy
Journal of Pharmacy and Pharmacology, 2007
The purpose of this review is to provide an insight into the different aspects of pH-sensitive liposomes. The review consists of 6 parts: the first introduces different types of medications made in liposomal drug delivery to overcome several drawbacks; the second elaborates the development of pH-sensitive liposomes; the third explains diverse mechanisms associated with the endocytosis and the cytosolic delivery of the drugs through pH-sensitive liposomes; the fourth describes the role and importance of pH-sensitive lipid dioleoylphosphatidylethanolamine (DOPE) and research carried on it; the fifth explains successful strategies used so far using the mechanism of pH sensitivity for fusogenic activity; the final part is a compilation of research that has played a significant role in emphasizing the success of pH-sensitive liposomes as an efficient drug delivery system in the treatment of malignant tumours. pH-Sensitive liposomes have been extensively studied in recent years as an amic...
On the formulation of pH-sensitive liposomes with long circulation times
Advanced Drug Delivery Reviews, 2004
Strategies used to enhance liposome-mediated drug delivery in vivo include the enhancement of stability and circulation time in the bloodstream, targeting to specific tissues or cells, and facilitation of intracytoplasmic delivery. pH-sensitive liposomes have been developed to mediate the introduction of highly hydrophilic molecules or macromolecules into the cytoplasm. These liposomes destabilize under acidic conditions found in the endocytotic pathway, and usually contain phosphatidylethanolamine (PE) and titratable stabilizing amphiphiles. Formulations without PE have also been developed. Encapsulated compounds are thought to be transported into the cytoplasm through destabilization of or fusion with the endosome membrane. Incorporation of a low mole percentage of poly(ethylene glycol) (PEG)-conjugated lipids into pHsensitive liposomes confers prolonged circulation times to these liposomes, which are otherwise cleared rapidly. While the incorporation of PEG -lipids reduces the pH-dependent release of encapsulated fluorescent markers in vitro, it does not hinder the cytoplasmic delivery of the markers per cell-associated liposome. This suggests that intracellular delivery is not dictated simply by the destabilization of the liposomes. Antibodies or ligands to cell surface receptors can be coupled to pH-sensitive or sterically stabilized pH-sensitive liposomes for targeting. pH-sensitive liposomes have been used to deliver anticancer drugs, antibiotics, antisense oligonucleotides, ribozymes, plasmids, proteins and peptides to cells in culture or in vivo. D
On the mechanisms of internalization and intracellular delivery mediated by pH-sensitive liposomes
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2001
We investigated the molecular mechanisms by which pH-sensitive liposomes surpass the cytoplasmic and endosomal membranes to deliver their aqueous contents into the cytoplasm. Various liposome formulations were evaluated for their efficacy to mediate intracellular delivery of encapsulated material, including a novel sterically stabilized pH-sensitive formulation ((DOPE:CHEMS:DSPE-PEG 2000 (6:4:0.3)) that was previously developed in our laboratories. In an attempt to fully characterize the nature of liposome^cell interactions different approaches based on a dual-labeling fluorescence assay were used. Our results indicate that the efficacy of interaction of pH-sensitive liposomes, both plain and sterically stabilized, with cells is strongly determined by the inclusion of DOPE in their composition, independently of the type of the amphiphilic stabilizer used. In fact, DOPE-containing liposomes shown to be non-pH sensitive by biophysical assays, mediated cytoplasmic delivery of their contents as efficiently as well known pH-sensitive formulations (e.g. DOPE:CHEMS). However, among the different formulations studied, DOPE:CHEMS liposomes were those exhibiting the highest extent of cell association. Moreover, our results with cells pretreated with metabolic inhibitors or lysosomotropic agents clearly indicate that DOPE-containing liposomes are internalized essentially by endocytosis and that acidification of the endosomes is not the only mechanism involved in the destabilization of the liposomes inside the cell. ß
Journal of Biological Chemistry, 1997
Liposomes that destabilize at mildly acidic pH are efficient tools for delivering water-soluble drugs into the cell cytoplasm. However, their use in vivo is limited because of their rapid uptake from circulation by the reticuloendothelial system. Lipid-anchored polyethylene glycol (PEG-PE) prolongs the circulation time of liposomes by steric stabilization. We have found that addition of PEG-PE to the membrane of pH-sensitive liposomes composed of cholesteryl hemisuccinate (CHEMS) and dioleoylphosphatidylethanolamine (DOPE) confers steric stability to these vesicles. This modification significantly decreases the pH-dependent release of a charged water-soluble fluorophore, calcein, from liposomes suspended in buffer or cell culture medium. However, the ability of such liposomes to release calcein intracellularly, measured by a novel flow cytometry technique involving dual fluorescence labeling, remains unaltered. As expected, the release of calcein from liposomes endocytosed by cells is inhibited upon pretreatment of the cells with NH 4 Cl, an inhibitor of endosome acidification. The unique properties of these liposomes were also demonstrated in vivo. The distribution kinetics of 111 In-containing CHEMS/DOPE/PEG-PE liposomes injected intravenously into rats has pharmacokinetic parameters similar to control, non-pH-sensitive, sterically stabilized CHEMS/distearoylphosphatidylcholine/PEG-PE liposomes. In contrast, regular pHsensitive liposomes lacking the PEG-PE component are cleared rapidly. Sterically stabilized pH-sensitive liposomes may therefore be useful for the intracellular delivery in vivo of highly negatively charged molecules such as genes, antisense oligonucleotides, and ribozymes for the treatment of various diseases.
Journal of Controlled Release, 2010
We developed pH-responsive liposomes containing synthetic glutamic acid-based zwitterionic lipids and evaluated their properties both in vitro and in vivo with the aim of constructing an efficient liposome-based systemic drug delivery system. The glutamic acid-based lipids; 1,5-dihexadecyl N-glutamyl-L-glutamate (L1) and 1,5-dihexadecyl N,N-diglutamyl-lysyl-L-glutamate (L2) were synthesized as a pH-responsive component of liposomes that respond to endosomal pH. The zeta potential of liposomes containing L1 or L2 was positive when the solution pH was below 4.6 or 5.6, respectively, but negative at higher pH values. The pH-responsive liposomes showed improved fusogenic potential to an endosome-mimicking anionic membrane at acidic pH, where the zeta potential of the liposomes was positive. We then prepared doxorubicin (DOX)-encapsulating liposomes containing L1 or L2, and clarified by confocal microscopic studies that the contents were rapidly transferred into both the cytoplasm and nucleus. Release of DOX from the endosomes mediated by the pHresponsive liposomes dramatically inhibited cancer cell growth. The L2-liposomes were slightly more effective than L1-liposomes as a drug delivery system. Intravenously injected L2-liposomes displayed blood persistence comparable to that of conventional phospholipid (PC)-based liposomes. Indeed, the antitumor efficacy of L2-liposomes was higher than that of PC-based liposomes against a xenograft breast cancer tumor in vivo. Thus, the high performance of L2-liposomes results from both efficient intracellular drug delivery and comparable blood persistence in comparison with the conventional PC-based liposomes in vitro and in vivo.
Trends and developments in liposome drug delivery systems
Journal of pharmaceutical sciences, 2001
Since the discovery of liposomes or lipid vesicles derived from self-forming enclosed lipid bilayers upon hydration, liposome drug delivery systems have played a signi®cant role in formulation of potent drugs to improve therapeutics. Currently, most of these liposome formulations are designed to reduce toxicity and to some extent increase accumulation at the target site(s) in a number of clinical applications. The current pharmaceutical preparations of liposome-based therapeutics stem from our understanding of lipid±drug interactions and liposome disposition mechanisms including the inhibition of rapid clearance of liposomes by controlling size, charge, and surface hydration. The insight gained from clinical use of liposome drug delivery systems can now be integrated to design liposomes targeted to tissues and cells with or without expression of target recognition molecules on liposome membranes. Enhanced safety and heightened ef®cacy have been achieved for a wide range of drug classes, including antitumor agents, antivirals, antifungals, antimicrobials, vaccines, and gene therapeutics. Additional re®nements of biomembrane sensors and liposome delivery systems that are effective in the presence of other membrane-bound proteins in vivo may permit selective delivery of therapeutic compounds to selected intracellular target areas. ß
Tumor-Targeted Immuno-liposomes for Delivery of Chemotherapeutics and Diagnostics
Journal of Pharmaceutical Innovation, 2008
The monoclonal antibody, mAb 2C5, recognizing the surface of numerous tumor, but not normal, cells via their surface-bound nucelosomes, was coupled onto sterically protected poly(ethylene glycol) liposomes. In this study, the development of different mAb 2C5-targeted formulations, like radiolabeled liposomes for gamma imaging of tumors and doxorubicin-containing liposomes for cancer chemotherapy, is described. Our data demonstrate the enhanced in vitro anticancer activities and the evident tumor-avid in vivo biodistribution, confirming the superior tumor-selectivity of the mAb 2C5-modified liposomes. This report reveals the eminent potential for this tumor-targeting strategy, with mAb 2C5, in improving the delivery of drugs and imaging agents into various tumors.
Liposome Technology for Cancer Treatment
The Bombay Technologist, 2020
Liposomes are microencapsulated and nano-encapsulated drug delivery systems. Liposomes are designed like a sandwich wherein the hydrophilic layer which contains the drug to be delivered at the target site is encapsulated between two hydrophobic layers. This enables efficient delivery of hydrophilic drugs through the body membranes which are lipophilic bio-membranes. The size of liposomes can be engineered according to the pore size of the target membranes. The development of the liposome technology has enabled to increase the therapeutic indices of agents mainly through alteration of biodistribution and bioavailability. The development of second generation liposomes from the existing liposomes is based on the conventional liposome systems. The second generation liposomes are long-circulating liposomes formed by modifying composition and length of the lipid chain and charge of the vesicle. Liposomes are gaining importance in targeted drug delivery, especially in cancer. The chemotherapy and radiotherapy used for treating cancer have multiple implications on the entire body. This is due to non-targeted treatment. The use of liposomes will help in identifying the cancerous cells selectively and thus can potentially reduce the extreme side effects of the medication. This selective nature is termed as 'ligand targeted therapeutics'. These ligands would be used to modify the liposomal surface to identify specific antigens of malignant cells. The advantages of liposomes in targeted delivery, along with the different categories of liposomes depending on size and lipid layers are discussed in this review.
pHLIP®-mediated delivery of PEGylated liposomes to cancer cells
Journal of Controlled Release, 2013
We develop a method for pH-dependent fusion between liposomes and cellular membranes using pHLIP (pH Low Insertion Peptide), which inserts into lipid bilayer of membrane only at low pH. Previously we establish the molecular mechanism of peptide action and show that pHLIP can target acidic diseased tissue. Here we investigate how coating of PEGylated liposomes with pHLIP might affect liposomal uptake by cells. The presence of pHLIP on the surface of PEGylated-liposomes enhanced membrane fusion and lipid exchange in a pH dependent fashion, leading to increase of cellular uptake and payload release, and inhibition of cell proliferation by liposomes containing ceramide. A novel type of pH-sensitive, "fusogenic" pHLIP-liposomes was developed, which could be used to selectively deliver various diagnostic and therapeutic agents to acidic diseased cells.
European Journal of Pharmaceutics and Biopharmaceutics, 2014
Stealth pH-responsive liposomes for the delivery of therapeutic proteins to the bladder epithelium were prepared using methoxy-poly(ethylene glycol) 5kDa-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (mPEG 5kDa-DSPE) and stearoyl-poly(ethylene glycol)-poly(methacryloyl sulfadimethoxine) copolymer (stearoyl-PEG-polySDM), which possesses an apparent pKa of 7.2. Liposomes of 0.2:0.6:100, 0.5:1.5:100 and 1:3:100 mPEG 5kDa-DSPE/stearoyl-PEG-polySDM/(soybean phosphatidylcholine + cholesterol) molar ratios were loaded with bovine serum albumin (BSA) as a protein model. The loading capacity was 1.3% w/w BSA/lipid. At pH 7.4, all liposome formulations displayed a negative zeta-potential and were stable for several days. By pH decrease or addition to mouse urine, the zeta potential strongly decreased, and the liposomes underwent a rapid size increase and aggregation. Photon correlation spectroscopy (PCS) and transmission electron microscopy (TEM) analyses showed that the extent of the aggregation depended on the stearoyl-PEG-polySDM/lipid molar ratio. Cytofluorimetric analysis and confocal microscopy showed that at pH 6.5, the incubation of MB49 mouse bladder cancer cells and macrophages with fluorescein isothiocyanate-labelled-BSA (FITC-BSA) loaded and N-(Lissamine Rhodamine B sulfonyl)-1, 2-dihexadecanoyl-sn-glycero-3phosphoethanolamine triethylammonium salt (rhodamine-DHPE) labelled 1:3:100 mPEG 5kDa-DSPE/stearoyl-PEG-polySDM/lipid molar ratio liposomes resulted in a time-dependent liposome association with the cells. At pH 7.4, the association of BSA-loaded liposomes with the MB49 cells and macrophages was remarkably lower than at pH 6.5. Confocal images of bladder sections revealed that 2 h after the instillation, liposomes at pH 7.4 and control non-responsive liposomes at pH 7.4 or 6.5 did not associate nor delivered FITC-BSA to the bladder epithelium. On the contrary, the pH-responsive liposome formulation set at pH 6.5 and soon administered to mice by bladder instillation showed that, 2 h after administration, the pH-responsive liposomes efficiently delivered the loaded FITC-BSA to the bladder epithelium.