Ki Young Choi†‡, Hong Yeol Yoon ‡§, Jong-Ho Kim⊥, Sang Mun Bae⊥ , Rang-Woon Park⊥, Young Mo Kang⊥, In-San Kim⊥, Ick Chan Kwon ‡, Kuiwon Choi ‡, Seo Young Jeong †, Kwangmeyung Kim ‡*, and Jae Hyung Park §*
Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 130-701, Republic of Korea
Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea
Department of Polymer Science and Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea
Cell & Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea
Correspondence to Jae Hyung Park, Kwangmeyung Kim
Tumor targetability and site-specific drug release of therapeutic nanoparticles are key factors for effective cancer therapy. In this study, poly(ethylene glycol) (PEG)-conjugated hyaluronic acid nanoparticles (P-HA-NPs) were investigated as carriers for anticancer drugs including doxorubicin and camptothecin (CPT). P-HA-NPs were internalized into cancer cells (SCC7 and MDA-MB-231) via receptor-mediated endocytosis, but were rarely taken up by normal fibroblasts (NIH-3T3). During in vitro drug release tests, P-HA-NPs rapidly released drugs when incubated with cancer cells, extracts of tumor tissues, or the enzyme Hyal-1, which is abundant in the intracellular compartments of cancer cells. CPT-loaded P-HA-NPs (CPT-P-HA-NPs) showed dose-dependent cytotoxicity to cancer cells (MDA-MB-231, SCC7, and HCT 116) and significantly lower cytotoxicity against normal fibroblasts (NIH-3T3) than free CPT. Unexpectedly, high concentrations of CPT-P-HA-NPs demonstrated greater cytotoxicity to cancer cells than free CPT. An in vivo biodistribution study indicated that P-HA-NPs selectively accumulated into tumor sites after systemic administration into tumor-bearing mice, primarily due to prolonged circulation in the blood and binding to a receptor (CD44) that was overexpressed on the cancer cells. In addition, when CPT-P-HA-NPs were systemically administrated into tumor-bearing mice, we saw no significant increases in tumor size for at least 35 days, implying high antitumor activity. Overall, P-HA-NPs showed promising potential as a drug carrier for cancer therapy.
Keywords: hyaluronic acid; nanoparticle; Hyal-1; camptothecin; drug release; tumor targeting