A Dendritic Polymer-Based Nanosystem Mediates Drug Penetration and Irreversible Endoplasmic Reticulum Stresses in Tumor via Neighboring Effect.

Nanoparticles (NPs)-based cancer therapeutics are generally impeded by poor drug penetration into solid tumors due to their dense tumor extracellular matrix (ECM). Herein, pH/redox-responsive dendritic polymer-based NPs are developed to amplify the neighboring effect for improving drug penetration and driving cell apoptosis via combination therapy. Pyropheophorbide a (Ppa) is conjugated with PEGylated dendritic peptides via disulfide bonds and doxorubicin (DOX) encapsulated in the conjugate to construct dual-responsive NPs, PDPP@D. Delayed released DOX and Ppa from PDPP@D exert their combination therapeutic effect to induce cell apoptosis, and then they are liberated out of dying cells to amplify the neighboring effect, resulting in their diffusion through the dense ECM and penetration into solid tumors. Transcriptome studies reveal that PDPP@D leads to irreversible stress on the endoplasmic reticulum and inhibits cell protection through blocking the IRE1-dependent survival pathway and unleashing the DR5-mediated caspase activity to promote cell death. The strategy of amplifying the neighboring effect of NPs through combination therapy may offer great potential in enhancing drug penetration and eradicating solid tumors.

A Transformable Amphiphilic and Block Polymer-Dendron Conjugate for Enhanced Tumor Penetration and Retention with Cellular Homeostasis Perturbation via Membrane Flow.

Efficient penetration and retention of therapeutic agents in tumor tissues can be realized through rational design of drug delivery systems. Herein, a polymer-dendron conjugate, POEGMA-b-p(GFLG-Dendron-Ppa) (GFLG-DP), is presented, which allows a cathepsin-B-triggered stealthy-to-sticky structural transformation. The compositions and ratios are optimized through dissipative particle dynamics simulations. GFLG-DP displays tumor-specific transformation and the consequently released dendron-Ppa is found to effectively accumulate on the tumor cell membrane. The interaction between the dendron-Ppa and the tumor cell membrane results in intracellular and intercellular transport via membrane flow, thus achieving efficient deep penetration and prolonged retention of therapeutic agents in the solid tumor tissues. Meanwhile, the interaction of dendron-Ppa with the endoplasmic reticulum disrupts cell homeostasis, making tumor cells more vulnerable and susceptible to photodynamic therapy. This platform represents a versatile approach to augmenting the tumor therapeutic efficacy of a nanomedicine via manipulation of its interactions with tumor membrane systems.