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Delivery of zoledronic acid encapsulated in folate-targeted liposomes results in potent in vitro cytotoxic activity on tumor cells.
J Control Release. 2010 May 9;
Authors: Shmeeda H, Amitay Y, Gorin J, Tzemach D, Mak L, Ogorka J, Kumar S, Zhang JA, Gabizon A
INTRODUCTION: Zoledronic acid (ZOL), a nitrogen-containing bisphosphonate, is a potent inhibitor of farnesyl-pyrophosphate synthase with poor in vitro cytotoxic activity as a result of its limited diffusion into tumor cells. The purpose of this study was to investigate whether liposomes targeted to the folate receptor (FR) can effectively deliver ZOL to tumor cells and enhance its in vitro cytotoxicity. METHODS: ZOL was entrapped in the water phase of liposomes of various compositions with or without a lipophilic folate ligand. Stability and blood levels after i.v. injection were checked. The in vitro cytotoxic activity and cell uptake of liposomal ZOL (L-ZOL) were examined on various human and mouse cell lines. RESULTS: All formulations were highly stable and resulted in high blood levels in contrast to free ZOL which was rapidly cleared from plasma. Nontargeted L-ZOL was devoid of any in vitro activity at concentrations up to 200microM. In contrast, potent cytotoxic activity of folate-targeted L-ZOL (FTL-ZOL) was observed, with optimal activity, reaching the sub-micromolar range, for dipalmitoyl-phosphatidylglycerol (DPPG)-containing liposomes and relatively lower activity for pegylated (PEG) formulations. IC50 values of FTL-ZOL on FR-expressing tumor cells were >100-fold lower than those of free ZOL. Compared to doxorubicin, the cytotoxicity of DPPG-FTL-ZOL was equivalent in drug-sensitive cell lines, and greatly superior in drug-resistant cell lines. When tested on the non-FR upregulated cell lines, the cytotoxicity of FTL-ZOL was lower but still superior to that of L-ZOL. The uptake of ZOL by FR-expressing tumor cells was enhanced approximately 25-fold with DPPG-FTL-ZOL, and only approximately 4-fold with PEG-FTL-ZOL. CONCLUSIONS: FR targeting of ZOL using liposomes is an effective means to exploit the tumor cell growth inhibitory properties of ZOL. DPPG-FTL-ZOL is significantly more efficient at intracellular delivery of ZOL than PEG-FTL-ZOL in FR-expressing tumor cells.
PMID: 20462513 [PubMed - as supplied by publisher]
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Sustained and specific in vitro inhibition of HIV-1 replication by a protease inhibitor encapsulated in gp120-targeted liposomes.
Antiviral Res. 2009 Nov;84(2):142-9
Authors: Clayton R, Ohagen A, Nicol F, Del Vecchio AM, Jonckers TH, Goethals O, Van Loock M, Michiels L, Grigsby J, Xu Z, Zhang YP, Gutshall LL, Cunningham M, Jiang H, Bola S, Sarisky RT, Hertogs K
Selective delivery of antiretrovirals to human immunodeficiency virus (HIV) infected cells may reduce toxicities associated with long-term highly active antiretroviral therapy (HAART), may improve therapeutic compliance and delay the emergence of resistance. We developed sterically stabilized pegylated liposomes coated with targeting ligands derived from the Fab' fragment of HIV-gp120-directed monoclonal antibody F105, and evaluated these liposomes as vehicles for targeted delivery of a novel HIV-1 protease inhibitor. We demonstrated that the immunoliposomes were selectively taken up by HIV-1-infected cells and localized intracellularly, enabling the establishment of a cytoplasmic reservoir of protease inhibitor. In antiviral experiments, the drug delivered by the immunoliposomes showed greater and longer antiviral activity than comparable concentrations of free drug or drug encapsulated in non-targeted liposomes. In conclusion, by combining a targeting moiety with drug-loaded liposomes, efficient and specific uptake by non-phagocytic HIV-infected cells was facilitated, resulting in drug delivery to infected cells. This approach to targeted delivery of antiretroviral compounds may enable the design of drug regimens for patients that allow increased therapeutic adherence and less toxic treatment of HIV infection.
PMID: 19699239 [PubMed - indexed for MEDLINE]
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Evaluation of encapsulated Newcastle disease virus liposomes using various phospholipids administered to improve chicken humoral immunity.
J Biomed Mater Res B Appl Biomater. 2009 Nov;91(2):621-5
Authors: Tseng LP, Chiou CJ, Deng MC, Lin MH, Pan RN, Huang YY, Liu DZ
We propose the adjuvant effects of phospholipid liposome compositions using intranasal inoculation of a liposomal-Newcastle disease virus (NDV) vaccine in chickens. The immunogenicity of three liposome formulations was determined in chickens using the hemagglutination-inhibition (HI) test, nasal secretory immunoglobulin A and serum immunoglobulin A (IgG) antibody titers using the enzyme-linked immunosorbent assay. The immune response against NDV antigens was determined after immunization with neutral charged liposomes composed of egg phosphatidylcholine (EPC) (60 micromol), cholesterol (Chol) (15 micromol), and EPC-liposomes (EPC-Lip), which elicited strong systemic (serum) and local (nasal) humoral responses. However, the intranasal administration with cationic charged liposomes composed of EPC (30 micromol), stearylamine (SA) (15 micromol), Chol (15 micromol), and SA-liposomes (SA-Lip) induced poor humoral immune responses. Only the vaccine formulated with anionic charged liposomes composed of EPC (30 micromol), dipalmitoylphosphatidylserine (15 micromol), Chol (15 micromol), and phosphatidylserine-liposomes (PS-Lip) elicited the highest titers of HI antibodies. These are the first results to suggest that antigen delivery using EPC-Lip is very useful in enhancing antibody production at the mucosal site and in serum.
PMID: 19582853 [PubMed - indexed for MEDLINE]
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