Endogenous Stimuli‐Sensitive Multistage Polymeric Micelleplex Anticancer Drug Delivery System for Efficient Tumor Penetration and Cellular Internalization

摘要: To efficiently deliver anticancer drugs to the entire tumor tissue and cancer cells, an endogenous stimuli-sensitive multistage polymeric micelleplex drug delivery system is developed via electrostatic complexation between poly(ethylene glycol)-block-poly[(N'-dimethylmaleoyl-2-aminoethyl)aspartamide]-block-poly(e-caprolactone) (PEG-b-PAsp(EDA-DM)-b-PCL) triblock copolymer micelles cisplatin prodrug (Pt(IV))-conjugated cationic poly(amidoamine) dendrimers (PAMAM-Pt(IV)). The micelleplexes maintain structural stability at pH 7.4 ensuring long blood circulation high accumulation level, while they exhibit triggered release of secondary PAMAM-Pt(IV) dendrimer nanocarriers tumoral acidity (≈pH 6.8) due acid-labile charge-reversal properties PAsp(EDA-DM) component under mildly acidic condition. released PAMAM with small size slightly positive charges significantly deep penetration efficient cellular internalization, followed by active in intracellular reducing medium. In vivo investigation reveals that Pt(IV)-loading suppress growth intravenous injection synergistic effect bloodstream, accumulation, penetration, internalization. Thus, stimuli-responsive feature show great potentials for better therapeutic efficacy especially through enhanced