A review of mechanistic insight and application of pH-sensitive liposomes in drug delivery

Figures & data

Figure 1. Selective uptake of liposomes by enhanced permeation and retention (EPR) effect. The disrupted endothelial lining allows entry of liposomes to tumor tissues and absence of lymphatic drainage support the retention of drugs in the tumor area hence called enhanced permeation and retention effect (EPR).

Figure 2. Targeted drug delivery from pH-sensitive liposome. (A) Mechanism involved in intracellular drug delivery; [1] Destabilization of pH-sensitive liposomes triggers the pore formation in endosomal membrane, [2] Destabilization of liposomes release the encapsulated molecules in endosome which diffuse to the cytoplasm through the endosomal membrane, [3] Fusion between the liposome and the endosomal membranes. (B) Localized delivery of anticancer drug to tumor site.

Table 1. List of recently published reports on pH-sensitive liposomes.

Drug	Delivery system	Concluding remarks	Reference
Doxorubicin	Multifunctional pH-sensitive immunoliposomes containing a pH-sensitive PEG-PE component, TATp, and the cancer cell-specific mAb 2C5	The nanocarrier demonstrated enhanced cytotoxicity and internalization by cancer cells.	Koren et al., 2012
Doxorubicin	Estrogen-anchored pH sensitive liposomes	The ES-pH-sensitive-SL efficiently suppressed the breast tumor growth in comparison to both ES-SL and free DOX. Serum enzyme activities such as LDH and CPK levels were also reduced suggesting reduced DOX induced cardiotoxicity.	Paliwal et al., 2012
Radioactive substance	PEG-folate-coated pH-sensitive liposomes	Animals treated with radioactive formulations showed a lower increase in tumor volume and a significantly higher percentage of necrosis compared with controls.	Soares et al., 2012
Deoxyribonucleic acid (DNA)	O-carboxymethyl-chitosan- cationic liposome-coated DNA/protamine/DNA complexes (CMCS-CLDPD)	In vitro and in vivo transfection studies confirmed that CMCS-CLDPD had pH-sensitivity and the outermost layer of CMCS fell off in the tumor tissue, which could not only protect CMCS-CLDPD from serum interaction but also enhance gene transfection efficiency.	Li et al., 2012
Therapeutic peptide	pH sensitive stealth liposomes	Therapeutic peptide encapsulated in pH-sensitive stealth liposomes was able to reach the nucleus of tumorigenic and non tumorigenic breast cancer cells.	Ducat et al., 2011
Cisplatin	pH-sensitive liposomes	Stealth pH-sensitive-CDDP significantly reduced the renal toxicity.	Leite et al., 2009
Ovalbumin (OVA)	pH-sensitive fusogenic polymer-succinylated poly(glycidol)-(SucPG-) modified liposomes	The results suggest that the pH-sensitive fusogenic polymer-(SucPG-) modified liposomes would serve effectively as an antigen delivery vehicle. Immunization with OVA-containing SucPG-modified liposomes resulted in the induction of OVA-specific IgG1, IgG2a, and IgG3 antibody response along with inducing Th1 and Th2 immune responses.	Watarai et al., 2013
Major histocompatibility complex (MHC) class I-restricted antigen	Cationic pH-sensitive liposomes	The exogenous protein antigen gained access to the class-I presentation pathway as the protein is introduced into the cytosolic compartment of the APC	Zhou et al., 1995
Man-LPR loaded with mRNA encoding a melanoma antigen	Mannosylated lipopolyplexes	The mRNA is formulated with histidylated liposomes and a histidylated polymer. These pH-sensitive liposomes promote membrane destabilization in endosomes upon the protonation of their histidine groups, allowed nucleic acid delivery in the cytosol. The DCs have been targeted via the mannose lipid incorporated in the liposomes.	Pichon et al., 2013
ISS-oligodeoxyribonucleotides (ODNs)	Listeriolysin O (LLO)-containing pH-sensitive liposomes	ISS-ODN in LLO-containing pH-sensitive liposomes yields a vaccine delivery system that enhances the cell-mediated immune response and skews this response toward the Th1-type	Andrews et al., 2012
HIV-1 V3 peptides	MPL adjuvanted pH-sensitive liposomes	liposomes composed of phosphatidylethanolamine-beta-oleoyl-gamma-palmitoyl (POPE)/cholesterol hemisuccinate (CHOH)/monophosphoryl lipid A (MPL) may be used as a potentially immunomodulating adjuvant system for the development of HIV and other viral vaccines.	Chang et al., 1999
Doxorubicin	Folate-poly(2-ethyl-2-oxazoline)-distearoyl phosphatidyl ethanolamine containing liposomes	A higher drug cumulative release from DOX-loaded liposomescontaining F-PEOz-DSPE or PEOz-DSPE in vitro was found in phosphate buffered saline at pH 5.0 medium than at pH 7.4. These results indicate that F-PEOz-DSPE exhibits selective targeting, pH-sensitivity and little cytotoxicity, and may be a promising polymeric material for dual receptor and pH-sensitive targeting liposome.	Xia et al., 2013
Temsirolimus	The amino acid-based lipids, 1,5-dioctadecyl-l-glutamyl 2-histidyl-hexahydrobenzoic acid (HHG2C(18)) and 1,5-distearyl N-(N-α-(4-mPEG2000) butanedione)-histidyl-l-glutamate (PEGHG2C(18)) containing liposomes	In vivo, CCI-779/PEGHG2C(18)-L after intravenous administration showed remarkably higher bioavailability and blood circulation time compared with unPEGylated CCI-779/HHG2C(18)-L, and had the strongest antitumor efficacy against xenograft renal tumor models.	Mo et al., 2013
pGPH1/GFP/Neo plasmid	Cationic liposomes composed of 3β-[N-(N′,N′-dimethylaminoethane) carbamoyl] cholesterol (DC-Chol) and dioleoylphosphatidylethanolamine (DOPE) (DC-Chol/DOPE)	The complex of DC-Chol/DOPE liposomes and pH-sensitive PEGylated liposomes showed enhanced accumulation in tumor tissue in vivo compared with DC-Chol/DOPE liposomes alone.	Chen et al., 2013

Table 2. Lipids or polymer used for the preparation of pH-sensitive liposomes.

S. No.	Lipid/polymer introduced for pH-sensitive character	Liposomal composition	Reference
1	PHC	Liposomes containing the pH-sensitive lipid PHC	Yatvin et al., 1980
2	pH-sensitive peptide GALA	pH-sensitive peptide GALA with DOTAP/DOPE	Subbarao et al., 1987
3	DOPE	pH-sensitive DOPE/CHEMS/PE–PEG liposomes	Woodle et al., 1992
4	Alkylated NIPAM copolymers	Alkylated NIPAM copolymers with EPC/Cholesterol liposomes	Zignani et al., 2000
5	POPE	POPE/CHOH/MPL	Chang et al., 2001
6	DDAB	EPC, DDAB, CHEMS and Tween-80	Shi et al., 2002
7	Diolein	Anionic pH-sensitive liposomes composed of diolein/CHEMS	Guo et al., 2002
8	SucPG	DPPC, DOPE, MPL, SucPG polymer	Watarai et al., 2013

DOPE: dioleoylphosphatidylethanolamine, EPC: egg phosphatidylcholine, CHEMS: Cholesteryl homosuccinate, DDAB: Dimethyldioctadecylammonium bromide, GALA: glutamic acid-alanine-leucine-alanine, NIPAM: Alkylated N-isopropylacrylamide, POPE: polyoleoylphosphatidylethanolamine, MPL: monophosphoryl lipid A, PHC: Palmitoyl homocysteine, SucPG: succinylated poly(glycidol), DPPC: Dipalmitoylphosphatidylcholine.

Table 3. List of patents on pH-sensitive liposomes.

S. No.	Patent No.	Title	Patent applicant
1	EP1438974 A2	pH-sensitive liposomes based on diacyl-glycero-phosphoethanolamine and diacyl-succinyl-glycerol	GE Healthcare As
2	EP0422543 A1	pH-sensitive liposomes	The Green Cross Coporation
3	US4925661A	Target-specific cytotoxic liposomes	Leaf Huang
4	US5786214A	pH-sensitive immunoliposomes and method of gene delivery to the mammalian central nervous system	Eric G Holmberg
5	US5965434A	Amphipathic pH sensitive compounds and delivery systems for delivering biologically active compounds	Vladimir Budker, Vladimir Gurevich, Jon A Wolff
6	US6426086B1	pH-sensitive, serum-stable liposomes	Demetrios Papahadjopoulos, Olivier Meyer, Jean-Christophe Leroux
7	US20040197392A1	pH-sensitive liposomes	Sigrid Fossheim, Knut-egil Loekling, Roald Skurtveit
8	WO2003032946A2	pH-sensitive liposomes for targeted drug delivery	Gertrude E Costin
9	2003/032946	pH-sensitive liposomes for targeted drug delivery	Petrescu Stefana, M Costin, Gertrude E Trif Mihaela, Nichita Norica, Dwek Raymond A
10	EP0983086	pH-sensitive liposomes and other types of encapsulated vaccines containing immunomodulators, and methods for making and using same	Jean-Claude Bystryn

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