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(ε-
caprolactone) (PEG-b-
PAsp(EDA-DM)-b-PCL) triblock copolymer
micelles and
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 and high
tumor accumulation level, while they exhibit triggered release of secondary PAMAM-Pt(IV)
dendrimer nanocarriers at tumoral acidity (≈pH 6.8) due to
acid-labile charge-reversal properties of
PAsp(EDA-DM) component under mildly acidic condition. The released PAMAM delivery nanocarriers with small size and slightly positive charges exhibit significantly deep
tumor tissue penetration and efficient cellular internalization, followed by release of active
cisplatin anticancer
drug in intracellular reducing medium. In vivo investigation reveals that the Pt(IV)-loading micelleplexes significantly suppress
tumor growth via
intravenous injection due to synergistic effect of long circulation in bloodstream, high
tumor accumulation, deep
tumor tissue penetration, and efficient cellular internalization. Thus, the micelleplexes with stimuli-responsive multistage release feature show great potentials for better therapeutic efficacy of
cancer especially through enhanced
tumor penetration and cellular internalization.