Polycarbonate-based ultra-pH sensitive nanoparticles improve therapeutic window

• Published in: Nature communications Vol. 11; no. 1; pp. 5828 - 12
• Main Authors: Wang, Xu, Wilhelm, Jonathan, Li, Wei, Li, Suxin, Wang, Zhaohui, Huang, Gang, Wang, Jian, Tang, Houliang, Khorsandi, Sina, Sun, Zhichen, Evers, Bret, Gao, Jinming
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 17.11.2020; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adjuvants, Immunologic - administration & dosage; Adjuvants, Immunologic - pharmacokinetics; Amplification; Animals; Antigens; Cancer Vaccines - administration & dosage; Cancer Vaccines - adverse effects; Cancer Vaccines - pharmacokinetics; Cell activation; Cell Line, Tumor; Cell-mediated immunity; Degradation; Diagnostic systems; Drug Delivery Systems; Hydrogen-Ion Concentration; Immunotherapy - methods; Inflammation; Inflammatory response; Interferon; Lymphocytes; Lymphocytes T; Magnetic Resonance Spectroscopy; Melanoma - therapy; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice, Inbred C57BL; Mice, Knockout; Nanomaterials; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - adverse effects; Nanoparticles - chemistry; Nanoparticles - therapeutic use; Nanotechnology; pH effects; Polycarbonate; Polycarbonate resins; Polycarboxylate Cement - chemistry; Polycarboxylate Cement - metabolism; Polyethylene Glycols - chemistry; Polymers; Polymers - chemical synthesis; Polymers - chemistry; Polymers - metabolism; Stimulators; Stimuli; T-Lymphocytes - immunology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19651-7

Stimuli-sensitive nanomaterials with cooperative response are capable of converting subtle and gradual biological variations into robust outputs to improve the precision of diagnostic or therapeutic outcomes. In this study, we report the design, synthesis and characterization of a series of degradable ultra-pH sensitive (dUPS) polymers that amplify small acidic pH changes to efficacious therapeutic outputs. A hydrolytically active polycarbonate backbone is used to construct the polymer with pH-dependent degradation kinetics. One dUPS polymer, PSC7A, can achieve activation of the stimulator of interferon genes and antigen delivery upon endosomal pH activation, leading to T cell-mediated antitumor immunity. While a non-degradable UPS polymer induces granulomatous inflammation that persists over months at the injection site, degradable PSC7A primes a transient acute inflammatory response followed by polymer degradation and complete tissue healing. The improved therapeutic window of the dUPS polymers opens up opportunities in pH-targeted drug and protein therapy.