Nanomedicines have been demonstrated to have passive or active tumor

targeting behaviors, which are promising for cancer chemotherapy. However,

most nanomedicines still suffer from a suboptimal targeting effect and drug

leakage, resulting in unsatisfactory treatment outcome. Herein, a hierarchical

responsive nanomedicine (HRNM) is developed for programmed delivery

of chemotherapeutics. The HRNMs are prepared via the self-assembly of

cyclic Arg-Gly-Asp (RGD) peptide conjugated triblock copolymer, poly(2-

(hexamethyleneimino)ethyl methacrylate)-poly(oligo-(ethylene glycol)

monomethyl ether methacrylate)-poly[reduction-responsive camptothecin]

(PC7A-POEG-PssCPT). In blood circulation, the RGD peptides are shielded

by the POEG coating; therefore, the nanosized HRNMs can achieve effective

tumor accumulation through passive targeting. Once the HRNMs reach a

tumor site, due to the hydrophobic-tohydrophilic conversion of PC7A chains

induced by the acidic tumor microenvironment, the RGD peptides will be

exposed for enhanced tumor retention and cellular internalization. Moreover,

in response to the glutathione inside cells, active CPT drugs will be released

rapidly for chemotherapy. The in vitro and in vivo results confirm effective

tumor targeting, potent antitumor effect, and reduced systemic toxicity of the

HRNMs. This HRNM is promising for enhanced chemotherapeutic delivery.