Synthesis of Carboxy-Dimethylmaleic Amide Linked Polymer Conjugate Based Ultra-pH-sensitive Nanoparticles for Enhanced Antitumor Immunotherapy.

Cytotoxic T lymphocytes (CTLs) are an important tool for anticancer immunotherapy. To elicit powerful CTL activities, ultra-pH-sensitive nanoparticles (NPs) based on methoxy poly(ethylene glycol)--[poly(diisopropylamino)ethyl methacrylate] have been synthesized as a vaccine delivery platform. A representative CTL epitope, ovalbumin (OVA) peptide antigen, was covalently conjugated to the polymer backbone through an acid responsive carboxy-dimethylmaleic amide linker (CDM) resulting in polymer P-CDM-OVA. Interestingly, while the P-CDM-OVA released OVA peptide slowly in a pH 6.4 buffer, the addition of bovine serum albumin (BSA) mimicking proteins encountered in a cellular and/or environment significantly accelerated the release process. Successful cell surface presentation of OVA was observed when P-CDM-OVA based ultra-pH-sensitive particles were incubated with antigen presenting cells. These P-CDM-OVA NPs greatly enhanced CTL responses compared to the free peptide or the previously reported acetalated dextran particles encapsulating OVA. The P-CDM was also investigated for adjuvant conjugation, and the coadministration of P-CDM-OVA and the P-CDM-adjuvant conjugate NPs further improved CTL responses and effectively reduced tumor growth in mice. Thus, the CDM linked polymer presents a promising platform for anticancer immunotherapy.