Biological Space 2/4: Targeted Drug DeliveryThursday, September 22, 2011, 12:30 - 13:00
Engineering nanobiopolymers based on poly(beta-L-malic acid) for tumor cell drug delivery and treatmentE. Holler*, H. Ding, K. Black, J. Ljubimova
Cedars-Sinai Medical Center (Los Angeles, US)
Objective: A new nanobioconjugate drug delivery platform poly(beta-L-malic acid) (PMLA) equipped with functional units for cancer intracellular drug delivery and cell/tissue targeting is introduced for treatment of brain and breast tumors in vivo. New drug variants have been engineered for systemic treatment of HER2-positive breast tumors to enhance the efficacy of trastuzumab/Herceptin®, of triple negative breast cancer, and of brain tumors including breast cancer metastases by drug design for crossing blood tumor barrier (BTB). Drug variants based on poly(beta-L-malic acid) have been called Polycefins . A choice of multiple drugs (including nucleic acids and proteins/peptides) and targeting molecules can be permanently fixed to the polymeric carrier. Examples of treatment are shown for HER2-positive breast tumor and for brain tumor. Methods: PMLA was obtained from Physarum polycephalum. Nanobioconjugates were characterized as to their molecular weight, size, and zeta-potential. Membranolytic activity was measured using artificial liposomes. Primary human glioma U87MG, T98G and breast tumor MDA-MB-231 and MDA-MB-474 cell lines were used for cytotoxicity assays and tumor treatment. In vivo imaging analysis and confocal microscopy were used to confirm tumor targeting and tissue distribution [2,3]. Results: Membranolytic activity was measured for two PMLA conjugates, P-LLL and P-LOEt [PMLA modified with pendant 40% trileucine (LLL) and 40% leucine ethyl ester (LOEt), respectively]. Only P-LLL induced significant liposome leakage at endosomal gradient pH (pH 5–6), but not at physiological pH 7.4. In vivo imaging revealed enhanced drug accumulation in tumors treated with the lead Polycefin compared to other treatments. The lead version bearing both Herceptin and antisense to HER2 produced strong sustained reduction of human breast tumor size in nude mice (90% less size vs. PBS treatment), compared to 50% size reduction by Polycefin with Herceptin alone (P<0.001). For brain cancer treatment, the drug variant crossed BTB and reduced intracranial brain tumor size 10-fold. Summary: Polycefin nanobioconjugates have a high potential in customized therapy.
. J.Y. Ljubimova and E. Holler. Nanomed. 3:247-265 (2008). . H. Ding and J.Y. Ljubimova. Proc Natl Acad Sci USA. 107:18143-18148 (2010). . S. Inoue and J.Y. Ljubimova. Cancer Res. 71:1454-1464 (2011). Grants: NIH/NCI R01CA123495, R01CA136841, U01CA151815, Winnick Foundation, M01RR00425, to JY Ljubimova
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