The goal of this project is to investigate the feasibility of treating drug-sensitive and multidrug resistant (MDR) cancers, which overexpress folate receptors (FR) using engineered pH-sensitive micelles. Our results demonstrated that 1) doxorubicin (DOX) loaded micelles were equally cytotoxic to sensitive MCF-7 (breast) and A2780 (ovarian) cancer cells and their MDR counterparts , 2) micelle formulations were cytotoxic to MDR cell lines with various unicellular MDR mechanisms (including Pgp, MRP, LRP, topoisomerase II, and bcl-2), 3) the formulations caused tumor regression of both MDR breast and ovarian tumor xenografts in a mouse model, 4) polymer cytotoxicity and apparent systemic toxicity were not observed. The mechanisms involved in these effects are three-fold: 1) active internalization via FR-mediated endocytosis, 2) pH-triggered release of DOX in endosomes and 3) endosomal membrane disruption caused by the polymeric components. These sequential events avoid ATP-driven efflux pumps, allow high cytosolic DOX concentrations and minimize drug sequestration/exocytosis. These combined effects overwhelm multifactorial defense mechanisms presented by MDR cells. In an effort to bring us closer to our long-term goal of clinical application, this renewal application intends to present the scale-up of polymer and micelles production, the development of paclitaxel loaded micelles in Part I, the evaluation of two micelle formulations (doxorubicin and paclitaxel) against resistant breast cancer and ovarian cancer tumors for preclinical studies in Part II, and formulation testing using more clinically relevant multidrug resistant cell or tissue models while considering the intracellular and intratumoral pharmacokinetics.
Unique pH-sensitive micelle/doxorubicin formulations tested in current funding period were found to be effective in tumor accumulation and killing various sensitive and multidrug resistant tumor cells in vitro and in vivo animal models. The research finalized a most effective formulation from animal studies along with systemic PK analysis. The results obtained strongly support the potential of preclinical investigation for future translational study. This competing renewal application thus proposes to develop the scale-up processes of polymers and micelles as well as a new micelle/paclitaxel formulation. Paclitaxel is a frontline chemotherapeutic for breast and ovarian cancers, which are current target diseases of the preclinical investigation. The preclinical study will include development of a powder formulation for storage, stability studies of the drug-loaded micelles in powder and in solution, toxicological evaluation, and an efficacy study. The research also plans to investigate more multidrug resistant models relevant to clinical setting and pharmacokinetic analysis at cellular and tissue levels.
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|Stirland, Darren Lars; Nichols, Joseph W; Miura, Seiji et al. (2013) Mind the gap: a survey of how cancer drug carriers are susceptible to the gap between research and practice. J Control Release 172:1045-64|
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|Gao, Zhong-Gao; Tian, Li; Hu, Jun et al. (2011) Prevention of metastasis in a 4T1 murine breast cancer model by doxorubicin carried by folate conjugated pH sensitive polymeric micelles. J Control Release 152:84-9|
|Kim, Dongin; Gao, Zhong Gao; Lee, Eun Seong et al. (2009) In vivo evaluation of doxorubicin-loaded polymeric micelles targeting folate receptors and early endosomal pH in drug-resistant ovarian cancer. Mol Pharm 6:1353-62|
|Yin, Haiqing; Bae, You Han (2009) Physicochemical aspects of doxorubicin-loaded pH-sensitive polymeric micelle formulations from a mixture of poly(L-histidine)-b-poly(ethylene glycol)/poly(L-lactide)-b-poly(ethylene glycol) [corrected]. Eur J Pharm Biopharm 71:223-30|
|Kang, Sun-Woong; Bae, You Han (2009) Cryopreservable and tumorigenic three-dimensional tumor culture in porous poly(lactic-co-glycolic acid) microsphere. Biomaterials 30:4227-32|
|Yin, Haiqing; Lee, Eun Seong; Kim, Dongin et al. (2008) Physicochemical characteristics of pH-sensitive poly(L-histidine)-b-poly(ethylene glycol)/poly(L-lactide)-b-poly(ethylene glycol) mixed micelles. J Control Release 126:130-8|
|Lee, Eun Seong; Gao, Zhonggao; Kim, Dongin et al. (2008) Super pH-sensitive multifunctional polymeric micelle for tumor pH(e) specific TAT exposure and multidrug resistance. J Control Release 129:228-36|
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