[Development of Tumor-targeting Drug Delivery Systems Based on an Understanding of Polymer Characteristics and the Tumor-specific Environment].

Tumor-specific active drug release from macromolecular antitumor drugs after tumor delivery is critical to achieve efficient cellular uptake of the active drug, thereby ensuring therapeutic efficacy. Upon reaching the tumor tissue, protease-facilitated depegylation of pegylated zinc protoporphyrin with ester bonds between PEG and ZnPP (esPEG-ZnPP) occurs, leading to a faster cellular uptake and superior antitumor efficacy compared to PEG-ZnPP with ether bonds (etPEG-ZnPP). This finding provides a viable strategy for achieving efficient tumor-specific drug release by utilizing an ester linkage between PEG and antitumor drugs. Another strategy involves using styrene-maleic acid copolymer (SMA), an amphiphilic polymer. Drug-encapsulating SMA aggregates disintegrate upon interaction with cell membrane components, releasing the encapsulated active drug. The author has demonstrated an improvement in the tumor accumulation of SMA-based macromolecular drugs by conjugating pirarubicin (THP), an anthracycline antitumor drug, with SMA. Furthermore, by conjugating various molecular weights of N-(2-hydroxypropyl)methacrylamide (HPMA) to THP via a hydrazone bond (P-THP, DP-THP, and SP-THP), the author has established a positive correlation between HPMA molecular weight and therapeutic efficacy as well as toxicity. Notably, P-THPs release THP under acidic conditions within tumor tissue; however, this release occurs solely outside tumor cells due to HPMA-mediated inhibition of cellular uptake. The author is currently developing macromolecular anticancer drugs using albumin for the tumor-targeted release of anticancer agents both intra- and extracellularly. The strategic development of tumor-targeting macromolecular antitumor drugs based on a comprehensive understanding of polymer characteristics and the tumor-specific environment is imperative for effective cancer therapy.