Dual endogenous stimuli-responsive polyplex micelles as smart two-step delivery nanocarriers for deep tumor tissue penetration and combating drug resistance of cisplatin

Massive delivery of therapeutics throughout tumors and efficient cellular internalization into tumor cells remain the major obstacles for polymeric drug delivery system in the treatment of drug-resistant cancers. To address these issues, we strategically programmed dual stimuli-responsive polyplex micelles as drug delivery systems from self-assembly of anionic block copolymers, poly(ethylene glycol)-poly[(N′-dimethylmaleoyl-2-aminoethyl)aspartamide] (PEG-PAsp(EDA-DM)), and platinum(IV)-conjugated cationic poly(amidoamine) (PAMAM–Pt(IV)) dendrimer prodrugs. It is noteworthy that the chemical design for anionic block copolymers affords intriguing charge conversional function in response to a mild acidic environment at the tumor site (pH ∼ 6.8), thereby permitting rapid disassembly of polyplex micelle as a result of electrostatic repulsion. Thus, PAMAM–Pt(IV) prodrugs released in the form of individual molecules exert deep penetration and good dispersion activity in the tumor tissue by virtue of their small size and high mobility. Furthermore, the well-dispersed positively charged PAMAM dendrimers owing to their high affinity to the negatively charged cellular membrane are efficiently internalized into the tumor cells, followed by release of active cisplatin drug in the reductive cytosol. Accordingly, the drug resistance of cisplatin can be addressed. This proof-of-concept anticancer drug delivery platform provides a unique two-step delivery of anti-cancer drugs for the pursuit of deep tumor tissue penetration and overcoming drug resistance.