Journal
BIOMATERIALS
Volume 35, Issue 37, Pages 9912-9919Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2014.08.029
Keywords
Cancer; Cationic polymer; Self-assembly; Necrosis; Antitumor immune responses
Funding
- Ministry of Health and Welfare of the Republic of Korea [A084060]
- Strategic Research through the National Research Foundation of Korea (NRF) - Korea government (MSIP) [2011-0028726]
- Directorate For Engineering
- Div Of Chem, Bioeng, Env, & Transp Sys [0747577] Funding Source: National Science Foundation
- Korea Health Promotion Institute [A084060] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Here, we report a self-assembled polymeric micellar immunomodulator (SPI) for enhanced cancer treatment based on cationic amphiphilic polymers. To obtain the cationic amphiphilic polymer, the hydrophobic all-trans-retinoic acid (ATRA) was conjugated with a hydrophilic low-molecular-weight PEI (LowPEI, M-n = 1.8 kDa). The ATRA-LowPEI conjugates could self-assemble in aqueous media, forming micelles with a strong positive charge (similar to+40 mV) and particle sizes of similar to 70 nm. Compared to conventional therapeutic agents (e.g., cisplatin), the SPI exhibited enhanced anti-cancer activity regardless of drug resistance. After mechanistic in vitro cell death studies, we revealed that the mechanical disruptive force generated by the cationic charge of SPI primarily induced necrotic cell death. Furthermore, the organelle fragments induced by the necrotic cell death triggered antitumoral immune responses. Therefore, SPI induced synergistic effects of the cationic charge-induced necrosis and antitumoral immune responses could produce an effective cancer treatment. In addition, the SPI was shielded by hyaluronic acid (HA/SPI complex) to enhance its tumor selectivity in vivo. Finally, the HA/SPI complex accumulated selectively into tumor sites after systemic administration into tumor-bearing mice, exhibiting effective antitumoral effects without systemic toxicity. Therefore, this technology holds great potential for translation into a clinical cancer treatment. (C) 2014 Elsevier Ltd. All rights reserved.
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