Targeted delivery of a guanidine-pendant Pt(iv)-backboned poly-prodrug by an anisamide-functionalized polypeptide

We describe here a novel targeting polyion complex (Tg-PIC) system for the delivery and intracellular release of cisplatin. Briefly, a guanidinium-pendant Pt(iv)-backboned poly-prodrug termed P(DSP-Gu) is prepared with excellent aqueous solubility, high drug-loading and high potency. To enable prolonged circulation and selective cellular internalization, P(DSP-Gu) is complexed with anisamide-end-capped poly(ethylene glycol)-block-poly(l-phosphotyrosine)-block-poly(l-leucine) (AA-PEG-PpY-PLeu) to yield Tg-PIC via electrostatic coacervation. Tg-PIC is stabilized by hydrogen bonding between phosphate and guanidinium, the PEG corona, and the helical poly(l-leucine) segment forming the hydrophobic core. The anisamide group, a high affinity ligand recognizing the sigma (σ) receptors that are overexpressed on many human malignancies including prostate cancer, is incorporated at the surface of the Tg-PIC for active targeting and efficient internalization. In vitro, the Tg-PICs show targeted and efficient internalization into sigma receptor-positive PC3 cells, and can release toxic Pt(ii) species due to the degradation of P(DSP-Gu) under the intracellular reducing conditions. In vivo, the Tg-PICs exhibit superior antitumor efficacy with reduced toxicity. Thus, the system holds considerable promise towards more effective and safe nanomedicine.