Tumour targetable and microenvironment-responsive nanoparticles simultaneously disrupt the PD-1/PD-L1 pathway and MAPK/ERK/JNK pathway for efficient treatment of colorectal cancer

Abstract

The present study was aimed to develop a novel combination therapeutic strategy of gene therapy and immunotherapy for efficiently treatment of colorectal cancer (CRC). To achieve that goal, the polyethylene glycol-modified poly (2-(N,N-dimethylamino) ethyl methacrylate) (PEG-PDMAEMA)-based nanoparticles loaded with protein tyrosine phosphatase non-receptor type 6 (PTPN6) (NP-PTPN6) was developed first followed by conjugation with anti-PD-L1 monoclonal antibodies (aPD-L1) atezolizumab (aPD-L1NP-PTPN6). Importantly, the aPD-L1 was conjugated on the surface of NP-PTPN6 by the matrix metalloproteinases (MMPs)-cleavable linkage PLGLAG. Therefore, the aPD-L1 would be completely released once the aPD-L1NP-PTPN6 was entrapped into tumour tissues as demonstrated by the release assay. Tumour targeting assay demonstrated the aPD-L1NP-PTPN6 have high affinity to CRC cells and resulted in excellent tumour targeting drug delivery efficacy. Additionally, anti-tumour effect evaluation revealed that the aPD-L1NP-PTPN6 has greater ability to inhibit the growth, invasion and migration of CRC cells and finally led to longer survival time of tumour-bearing mice than other treatments. Further mechanisms studies demonstrated that treatment of CRC cells with aPD-L1NP-PTPN6 contributed to significant suppression of the MAPK/ERK signalling pathway. Besides, it was further demonstrated that treating CRC with aPD-L1NP-PTPN6 resulted in up-regulation of NK cells and T cells percentage within the tumour tissues.

Keywords:

• Combination therapeutic strategy
• gene therapy
• nanoparticles
• tumour targeting
• matrix metalloproteinase

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Disclosure statement

The authors declare no competing financial interests.