Microenvironment Induced in Situ Self-Assembly of Polymer-Peptides Conjugates that Attack Solid Tumor Deeply.

Nanoparticles preferentially target and accumulate in tumor due to the abnormality of tumor vasculature. However, unsatisfactory solid tumor penetration somewhat limits the therapeutic efficacy. Herein, by employing 'in vivo self-assembly' strategy, we have designed an acid-induced hydrophobicity-increasing polymer-peptide conjugates (PPCs) with narrow pH response range (from 7.4 to 6.5) under proper molecular concentration (around IC50 of PPCs), successfully realizing in-situ self-assembly process in tumor microenvironment for tumor-deeper drug delivery. A cytotoxic peptide KLAK, decorated by a pH-sensitive moiety cis-aconitic anhydride (CAA), and a cell-penetrating peptide TAT, are conjugated onto the poly(β-thioester)s backbones to gain PT-K-CAA that can penetrates deeply into solid tumor due to its small size as a single chain. During the penetration in vivo, CAA responses to the weak acid, leading to self-assembly of PPCs and the recovery of therapeutic activity. Therefore, deep-penetration ability for enhanced cancer therapy of peptide nanomaterials is provided by this in-vivo assembly strategy.