PhAc-ALGP-Dox

Chemotherapy remains the primary treatment modality for breast cancer (BCa) patients. However, chemoresistance commonly arises in clinical settings, contributing to poor prognosis. The development of chemoresistance is a dynamic and complex process involving the activation of oncogenes and inactivation of tumor suppressor genes. In this work, we utilized the RNA-sequencing (RNA-seq) technology to analyze the gene expression profiles of primary and recurrent tumor samples from BCa patients received the postoperative standard chemotherapy with doxorubicin (DOX), and identified glutathione S-transferase P1 (GSTP1) as a key factor in regulating chemoresistance. Molecular mechanistic studies revealed that high GSTP1 expression could not only impair the cytotoxicity of DOX by catalyzing the conjugation of reductive glutathione (GSH) with DOX, but also block the c-Jun NH2-terminal kinase (JNK) pathway to promote the proliferation via up-regulating anti-apoptotic B-cell lymphoma-2 (Bcl-2) expression. Given the severe side effects of DOX and the potential of RNA interference (RNAi) technology to silence target gene expression, we developed an endosomal pH-responsive nanoparticle (NP) platform for systemic co-delivery of DOX and GSTP1 siRNA (siGSTP1), and demonstrated its efficacy in reversing chemoresistance and suppressing the growth of DOX-resistant BCa tumors.

The excessive extracellular matrix (ECM) in solid tumors significantly inhibits the deep penetration and homogeneous distribution of nanodrugs, which greatly reduces the therapeutic efficacy. In the present work, an injectable polyelectrolyte hydrogel (CD@IPH) containing collagenase and doxorubicin-loaded polyacrylic acid@polyaniline nanoparticles (DOX@NP) were developed for improved photothermal and chemotherapy. The collagenase is released quickly from the polyelectrolyte hydrogel in the first 12 h, effectively degrading ECM and enhancing the deep penetration and evenly distribution of DOX@NP in tumor tissues. Then, the tumor microenvironment-triggered release of DOX from DOX@NP exhibits improved photothermal and chemotherapeutic efficiency. Owing to the excellent photoacoustic and photothermal properties of polyaniline inner cores of DOX@NP, the drug penetration process can be monitored to enable the image-guided cancer therapy. Both in vitro and in vivo assays prove the superior therapeutic efficacy of collagenase-enhanced photothermal and chemotherapy. The designed nanocomposite hydrogel therefore provides a versatile drug delivery system for deep tumor synergistic therapies.