Concomitant inhibition of PARP and PI3K pathways has
been recognized
as a promising strategy for cancer therapy, which may expand the clinical
utility of PARP inhibitors. Herein, we report the discovery of dual
PARP/PI3K inhibitors that merge the pharmacophores of PARP and PI3K
inhibitors. Among them, compound 15 stands out as the
most promising candidate with potent inhibitory activities against
both PARP-1/2 and PI3Kα/δ with pIC50 values
greater than 8. Compound 15 displayed superior antiproliferative
profiles against both BRCA-deficient and BRCA-proficient cancer cells
in cellular assays. The prominent synergistic effects produced by
the concomitant inhibition of the two targets were elucidated by comprehensive
biochemical and cellular mechanistic studies. In vivo, 15 showed more efficacious antitumor activity than the corresponding
drug combination (Olaparib + BKM120) in the MDA-MB-468 xenograft model
with a tumor growth inhibitory rate of 73.4% without causing observable
toxic effects. All of the results indicate that 15, a
first potent dual PARP/PI3K inhibitor, is a highly effective anticancer
compound.
Indoleamine
2,3-dioxygenase-1 (IDO1) plays an important role in
tumor immune escape. However, unsatisfactory clinical efficacies of
selective IDO1 inhibitors have impeded their further development,
suggesting that they do not exert sufficient antitumor effects by
selectively inhibiting IDO1. IDO2, an isoenzyme of IDO1, is overexpressed
in some human tumors, and emerging evidence suggests that concomitant
inhibition of IDO1/2 may have synergistic effects in cancer treatment,
revealing a promising cancer immunotherapeutic strategy. Herein, we
describe the discovery of compound 4t, the first inhibitor
targeting both IDO1/2 that has excellent in vitro inhibitory activity (IDO1 IC50 = 28 nM and IDO2 IC50 = 144 nM). Notably, 4t (TGI = 69.7%) exhibited
significantly stronger in vivo antitumor potency
than epacadostat (TGI = 49.4%) in CT26 xenograft mouse models, highlighting
the advantages of IDO1/2 dual inhibitors for tumor immunotherapy.
Preliminary mechanistic studies in vivo further identified
that 4t exerts its antitumor effect by inhibiting IDO1/2.
Transarterial chemoembolization (TACE) has been widely introduced to treat hepatocellular carcinoma (HCC) especially for unresectable patients for decades. However, TACE evokes an angiogenic response due to the secretion of vascular endothelial growth factor (VEGF), resulting in the formation of new blood vessels and eventually tumor recurrence. Thus, we aimed to develop regorafenib (REGO)-loaded poly (lactide-co-glycolide) (PLGA) microspheres that enabled localized and sustained drug delivery to limit proangiogenic responses following TACE in HCC treatment. REGO-loaded PLGA microspheres were prepared using the emulsion-solvent evaporation/extraction method, in which DMF was selected as an organic phase co-solvent. Accordingly, we optimized the proportion of DMF, which the optimal ratio to DCM was 1:9 (v/v). After preparation, the microspheres provided high drug loading capacity of 28.6%, high loading efficiency of 91.5%, and the average particle size of 149 µm for TACE. IR spectra and XRD were applied to confirming sufficient REGO entrapment. The
in vitro
release profiles demonstrated sustained drug release of microspheres for more than 30 d To confirm the role of REGO-loaded microspheres in TACE, the cell cytotoxic activity on HepG2 cells and anti-angiogenic effects in HUVECs Tube-formation assay were studied in combination with miriplatin. Moreover, the microspheres indicated the potential of antagonizing miriplatin resistance of HepG2 cells
in vitro
. Pharmacokinetics preliminary studies exhibited that REGO could be sustainably released from microspheres for more than 30 d after TACE
in vivo. In vivo
anti-tumor efficacy was further determined in HepG2 xenograft tumor mouse model, demonstrating that REGO microspheres could improve the antitumor efficacy of miriplatin remarkably compared with miriplatin monotherapy. In conclusion, the obtained REGO microspheres demonstrated promising therapeutic effects against HCC when combined with TACE.
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