As a potential cancer immunotherapeutic agent, CHA has entered phase II clinical trials in China as a lyophilized powder formulation for treating glioma. However, the in vivo instability of CHA necessitates daily intramuscular injections, resulting in patient noncompliance. In this study, CHA-phospholipid complex (PC)-containing PEGylated liposomes (CHA-PC PEG-Lipo, named as CPPL), with CHA-PC as the drug intermediate, were prepared to lower the administration frequency. CPPL demonstrated excellent physicochemical properties, enhanced tumor accumulation, and inhibited tumor growth even when the administration interval was prolonged to 4 days when compared to a CHA solution and CHA-PC loaded liposomes (CHA-PC Lipo, labeled as CPL), both of which only demonstrated antitumor efficacy with once-daily administration.

Further evaluation of the in vivo antitumor immune mechanism suggested that the extended antitumor immune efficacy of CPPL could be attributed to its distinct immune-stimulating mechanism when compared with CHA solution and CPL, such as stimulating both CD4+ and CD8+ T cell infiltration, inhibiting myeloid-derived suppressor cell expression, reducing the expression of Th2 related factors, and notably, increasing the memory T cells in tumor tissues. This CHA-containing formulation could reduce the frequency of in vivo CHA administration during cancer treatment via T cells, especially memory T cell regulation.

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