Long-circulating liposomes coated with amphiphilic derivatives of certain soluble polymers have high potential as drug carriers. They increase the duration of drug action, decrease toxicity of various drugs, and are able to accumulate non-specifically in tissues with leaky vasculature (infarcts and tumors). Targeted long- circulating liposomes can be made by simultaneous attachment of specific ligands (monoclonal antibodies) onto their surface or directly only distal termini of liposome-grafted protecting polymers. We have designed a set of polymers to be used as liposome steric protectors and developed a simple and fast method for the attachment of specific ligands, including monoclonal antibodies, to distal termini of polymeric chains via p- nitrophenylcarbonyl (pNP) group. Such sterically-protected targeted liposomes demonstrated superior properties including target accumulation compared with plain liposomes, immunoliposomes or long-circulating liposomes both in vitro and in vivo. We hypothesize that: i. Drug-loaded long-circulating targeted liposomes can provided higher therapeutic effects compared with other liposome-based drug delivery systems; ii. Experimental myocardial infarction and tumors represent convenient models for studies with drug-loaded long- circulating immunoliposomes; iii. Long-circulating infarct- specific anti-myosin immunoliposomes loaded with ATP or coenzyme Q10 can diminish heart damage upon induced ischemia in vitro and in vivo; iv. Long-circulating tumor-specific anti-nucleosome immunoliposomes loaded with doxorubicin can enhance tumor cell killing in vivo. The use of new general approaches a new polymers for the preparation of polymer- modified long-circulating (targeted) liposomes may increase the potential of liposomes as drug carriers as well as the therapeutic efficacy of liposome-entrapped drugs. To test our hypothesis, we plan: (1) To prepare a set of long- circulating immunoliposomes coated with protecting polymers and antimyosin or anti-nucleosome antibody attached to distal end of the liposome surface-grafted polymer via p-NP- group, and load liposomes with ATP or coenzyme Q10 (for infarct-related experiments) and with doxorubicin (for a few cancer-related experiments); (2) To study the ability of long-circulating anti-myosin immunoliposomes to deliver ATP or coenzyme Q10 to affected areas and decrease damage to the heart in a model of ischemia in perfused isolated rat and rabbit heart in vitro and in a model of experimental myocardial infarction in rabbits in vivo; (3) To study the ability of long-circulating anti-nucleosome liposomes to deliver higher quantities of anticancer drug doxorubicin to cancer cells and increase the level of cell death in growing murine tumor in C57BL mice and human tumor in nude mice. This study could bring to life new liposomal drugs with controlled in vivo stability and biodistribution. Specifically, liposomal drugs can be prepared for the treatment of the consequences of myocardial ischemia and for the inhibition of tumor growth.
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