Targeting of anticancer agents to cancer cells increases efficacy and reduces systems side effects of the treatment. The general aim of this project is to develop an improved targeted therapy for cancer by creating a pharmaceutical carrier with efficient delivery to a tumor and increased bioavailability of the delivered agent.
This aim will be approached on the basis of a recently introduced drug carrier, sterically stabilized liposomes (SSL), that has already demonstrated long circulation lifetimes and increased accumulation in malignant tumors. However, the longevity of SSL in circulation calls for stable retention of the carried anticancer agent within the liposomes, which contradicts the requirement for bioavailability of the agent to tumor cells. The hypothesis is that this contradiction can be resolved by, first, targeting SSL to cancer cells via attachment of molecules that cause cell-specific binding and internalization of drug-loaded SSL, to a clinically achievable and acceptable increase in tumor temperature. Thus, raising the tumor temperature after administration of drug carried by such SSL will trigger massive drug release inside target cancer cells, while at normal physiological temperature the drug will remain stably entrapped in the carrier. Although preliminary studies have established a methodological basis for both tumor-targeted SSL and temperature-sensitive SSL, the synthesis of SSL combining both properties has not yet been achieved. This application proposes: (1) to synthesize cancer cell-targeted temperature-sensitive SSL (ttsSSL) by attachment of a tumor-specific antibody fragment or a folic acid molecule; (2) to quantify binding and internalization of such ttsSSL by target cells in vitro using live cell spectrofluorometry of a ttsSSL-entrapped pH-sensitive fluorophore; (3) to load ttsSSL with an anticancer drug, doxorubicin, and study the effect of thermally triggered intracellular drug release on the cytotoxicity of doxorubicin-loaded ttsSSL in target-competent cancer cells in vitro; (4) to study the pharmacokinetics and antitumor efficacy of ttsSSL against human tumor xenografts in nude mice. This study will provide a basis for further preclinical studies on targeted intracellular delivery of other cytostatics, anticancer toxins and genes, and, eventually, for translation of the proposed methodology to the clinic.
|Nielsen, Ulrik B; Kirpotin, Dmitri B; Pickering, Edward M et al. (2002) Therapeutic efficacy of anti-ErbB2 immunoliposomes targeted by a phage antibody selected for cellular endocytosis. Biochim Biophys Acta 1591:109-118|
|Drummond, D C; Hong, K; Park, J W et al. (2000) Liposome targeting to tumors using vitamin and growth factor receptors. Vitam Horm 60:285-332|