Enhanced drug release from a pH-responsive nanocarrier can augment colon cancer treatment by blocking PD-L1 checkpoint and consuming tumor glucose. (July 2022)

• Record Type: Journal Article
• Authors: Guo, Kai; Liu, Yixuan; Ding, Min; Sun, Qi; Shubhra, Quazi T.H.
• Is Part Of: Materials & design. Volume 219(2022)
• Publication Date: 2022-07
• Subjects: Nanocarrier -- Cancer immunotherapy -- Glucose oxidase -- Immune activation -- Checkpoint inhibition -- T cell; Materials -- Periodicals; Engineering design -- Periodicals; Matériaux -- Périodiques; Conception technique -- Périodiques; Electronic journals; 620.11
• DOI: 10.1016/j.matdes.2022.110824
• Languages: English
• ISSNs: 0264-1275

Abstract

Graphical abstract: Highlights: Activation of immune system and tumor glucose consumption efficiently treat cancer. PD-L1 checkpoint protein inhibition can help T cell to kill cancer cell. This study reports starvation-immunotherapy combination to treat colon cancer. In acidic environment, prepared nanoparticles showed accelerated drug release. Abstract: In this study, it was aimed to exploit no chemical drug to treat cancer by starvation-immunotherapy combination. We used PD-L1 siRNA to down-regulate checkpoint protein PD-L1 on cancer cell surfaces, and IFN-γ was used as an immunomodulatory agent to activate the innate immune system. When PD-L1 siRNA, IFN-γ, and glucose oxidase (GOx) were co-delivered to the tumor microenvironment (TME) by a pH-sensitive drug delivery system (DDS), starvation-immunotherapy combinedly resulted in significant tumor volume reduction in a mouse model. The DDS was prepared by using PLGA polymer whose surface was coated with chitosan. IFN-γ, siRNA, and GOx entrapment efficiencies were 93.5 ± 3.1%, 65.1 ± 2.6%, and 66.2 ± 3.3%, respectively. Moreover, the size of the DDS was well below 200 nm, allowing easy sterilization and tumor accumulation by the enhanced permeability and retention (EPR) effect. In vitro pH-dependent release study indicated that in acidic pH, the developed DDS can show accelerated drug release. In a mouse model and in acidic TME, the DDS resulted in the best therapeutic effect due to pH-dependent drug release compared to unmodified DDS and free drug. Our findings reflect that high efficiency in colon cancer treatment is achieved by combination therapy over the studied monotherapies.