Enzyme-activatable disk-shaped nanocarriers augment tumor permeability for breast cancer combination therapy

Unique physiopathological characteristics of tumor tissues impose obstacles to the sufficient penetration of traditional nanomedicines, resulting in undesirable drug delivery efficacy and therapeutic outcomes. Here, we constructed TRAIL-[ND-HCPT]GAC, a synergistic hydroxycamptothecin (HCPT) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein co-loaded disk-shaped nanocarrier with γ-glutamyl transpeptidase responsiveness. When the novel nanodisks extravasated into the tumor interstitium, the γ-glutamyl transpeptidase overexpressed on the tumor cell membranes cleaved the γ-glutamyl portions of the nanodisk surface to produce positively charged amino groups. As a result, the cationic nanodisks possessed stronger tumor infiltration ability through transcytosis than anionic nanodisks. HCPT and TRAIL exerted synergistic antitumor effects with better overall therapeutic efficacy. This TRAIL-[ND-HCPT]GAC system performed significantly better than free HCPT and remarkably prolonged the survival of breast tumor-bearing mice with no significant toxicity.