Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 7, Issue 12, Pages 6661-6673Publisher
AMER CHEMICAL SOC
DOI: 10.1021/am509204u
Keywords
combination therapy; prostate cancer; HPMA copolymer; G3-C12; synergistic genotoxicity
Funding
- National Natural Science Foundation of China [81473167]
- Doctoral Fund of Ministry of Education of China [2013018111001]
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To improve the therapeutic efficacy of anticancer combination therapy, we designed a nanoplatform based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers that allows covalent bonding of two chemotherapeutics acting via different anticancer mechanisms and that can enter target cells by receptor-mediated endocytosis. Doxorubicin (DOX) was covalently conjugated to a nanosized HPMA copolymer using a pH-sensitive hydrazone bond and 5-fluorouracil (5-Fu) was conjugated to the same backbone using an enzymatically degradable oligopeptide Gly-Phe-Leu-Gly sequence. Then, the conjugate was decorated with galectin-3 targeting peptide G3-C12 [P-(G3-C12)-DOX-Fu]. The two drugs showed similar in vitro release profiles, suggesting that they may be able to work synergistically in the codelivery system. In galectin-3 overexpressed PC-3 human prostate carcinoma cells, P-(G3-C12)-DOX-Fu surprisingly exhibited comparable cytotoxicity to free DOX at high concentration by increasing cell internalization and exerting synergistic genotoxic effects of cell cycle arrest, caspase-3 activation, and DNA damage. In mice bearing PC-3 tumor xenografts, the use of tumor-targeting ligand substantially enhanced the intracellular delivery of P-(G3-C12)-DOX-Fu in tumors. The targeted dual drug-loaded conjugate inhibited tumor growth to a greater extent (tumor inhibition of 81.6%) than did nontargeted P-DOX-Fu (71.2%), P-DOX (63%), DOX center dot HCl (40.5%), P-Fu (32.0%), or 5-Fu (14.6%), without inducing any obvious side effects. These results demonstrate the potential of synergistic combination therapy using targeted nanocarriers for efficient treatment of prostate cancer.
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