Degradable Mesoporous Silica Nanoparticle/Peptide-Based “Trojan Horse”-like Drug Delivery System for Deep Intratumoral Penetration and Cancer Therapy

For conventional anticancer drug delivery systems (DDSs), it is difficult to endow them with both long circulation in vivo and easy cellular endocytosis by cancer cells as well as the ability to accumulate in tumors through the enhanced permeability and retention (EPR) effect and deep intratumoral penetration. Therefore, their in vivo treatment effects are inadequate. Previous studies have shown that "dynamic protection" strategies can effectively address the difficulty of DDS entry into cancer cells as a result of modifying "stealthy" molecules such as poly(ethylene glycol) (PEG). In this work, a "Trojan horse"-like DDS was fabricated by employing the "dynamic protection" strategy. The DDS was developed using ultrasmall, degradable mesoporous silica nanoparticles (DS-MSN) that were bridged by a degradable peptide and cross-linked with 4-arm PEG-N3 through click chemistry. This resulted in DOX-DS-MSN-CD-peptide-PEG with a size of ∼300 nm, which could accumulate in the tumor, following adequate blood circulation. The peptide could be degraded by matrix metalloproteinase-2 (MMP-2), an overexpressed enzyme in tumors, leading to the release of small-sized, tumor-permeable DS-MSN-based carriers. The remaining Arg-Gly-Asp (RGD) peptide on the surface provides the carriers with a "tumor-triggered targeting" capability. DS-MSN, which includes disulfide bonds in its backbone, could be degraded due to glutathione (GSH) in cancer cells and release of the loaded doxorubicin hydrochloride (DOX). In vitro and in vivo experiments showed that DOX-DS-MSN-CD-peptide-PEG had a prolonged circulation time and tumor accumulation ability, excellent tumor penetration ability, and controlled drug release ability. It operated like a "Trojan horse", overcoming obstacles to deliver the "Greek soldier" DOX to the interior of cancer cells, resulting in effective tumor suppression. This study offers interesting concepts for designing effective and safe drug delivery systems.