Delivery of PARP inhibitors through 2HG-incorporated liposomes for synergistically targeting DNA repair in cancer.

PARP inhibitors (PARPi) benefit only a small subset of patients with DNA homologous recombination (HR) defects. In addition, long-term administration of a PARPi can lead to the development of drug resistance. 2-Hydroxyglutarate (2HG) has long been known as an oncometabolite but is capable of inducing an HR defect, which makes tumor cells exquisitely sensitive to PARPi. To facilitate the translation of this discovery to the treatment of both HR-deficient and HR-proficient tumors, a liposomal formulation was developed for codelivery of 2HG and veliparib, a PARPi. A sequential loading protocol was developed such that the initial loading of 2HG into liposomes greatly facilitated the subsequent, pH gradient-driven remote loading of veliparib. The liposomes co-loaded with veliparib and 2HG exhibited favorable stability, slow kinetics of drug release, and targeted delivery to the tumor. Furthermore, the veliparib/2HG liposomes demonstrated enhanced anti-tumor activity in both PARPi-resistant BRCA mutant cancer and BRCA wildtype cancer by synergistically enhancing the defect in DNA repair. Moreover, combination of veliparib and 2HG via liposomal co-delivery also augmented the function of cytotoxic T cells by activating the STING pathway and downregulating PD-L1 expression via 2HG-induced hypermethylation.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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