Lysosome activable polymeric vorinostat encapsulating PD-L1KD for a combination of HDACi and immunotherapy

Abstract

PD-1/PD-L1 blocking therapy has become one of the most promising methods in the field of tumor treatment. However, it encounters the challenge of immune escape due to the exhaustion of T cells. Studies have shown that the epigenetic regulation drug histone deacetylase inhibitor (HDACi) may be able to reverse exhausted T cells by changing the epigenetic transcription program. Therefore, the combination of epigenetic therapy and PD-1/PD-L1 blockade therapy is expected to reverse the immune escape, whereas the overriding goal should aim at the spontaneous release and synergy of PD-1/PD-L1 blocking siRNA and HDACi. In this study, we develop PDDS{polyethylene glycol-b-asparaginate(diethylenetriamine-vorinostat), (PEG-b-P[Asp(DET-SAHA) n ] PPDS)}encapsulating siRNA-PD-L1to provide micelles siRNA-PD-L1-loaded micelles (siRNA@PPDS). Transmission electron microscope (TEM) images demonstrate that siRNA@PPDS micelles presented spherical morphology with a size of about 120 nm; hydrodynamic data analysis indicates pH sensitivity of siRNA@PPDS micelles. The experiments reveal that siRNA@PPDS micelles could be well uptaken by the tumor cells to silence the expression of PD-L1 protein in a dose-dependent manner; compared with the free SAHA, the SAHA-loaded micelles PPDS show higher cytotoxicity to induce tumor cell apoptosis and block cell cycle in G1 phase on melanoma-bearing mice, siRNA@PPDS has shown outstanding inhibition of tumor growth and pulmonary metastasis. By comprehensively activating the immune system, lysosome activable polymeric vorinostat encapsulating PD-L1KD for the combination therapy of PD-L1-KD and HDACIs can be an effective strategy to reverse the unresponsiveness of immune checkpoint inhibitors and a promising treatment to inhibit tumor growth, recurrence, and metastasis in clinic.

Ibrutinib combined with low‐dose histone deacetylases inhibitor chidamide synergistically enhances the anti‐tumor effect in B‐cell lymphoma

“…[38][39][40][41] HDAC inhibitors have exerted promising anti-tumor effects in combination with traditional chemotherapy or molecular inhibitors in hematological malignancies. 13,[42][43][44][45] We discovered that chidamide treatment activated BTK, which was consistent with a previous report. 43 Based on this result and the widely known effects of BTK inhibitor ibrutinib, we chose to combine ibrutinib with the HDAC inhibitor chidamide.…”

“…[8][9][10] Recently, HDAC inhibitors have been shown to improve tumor immunogenicity, enhance anti-tumor immunity, or reverse immunosuppressive tumor microenvironments. [11][12][13] However, the use of HDAC inhibitors has been restricted due to primary or secondary resistance. Therefore, combined therapy of HDAC inhibitors with other appropriate agents should be investigated.…”

Redox-sensitive iodinated polymersomes carrying histone deacetylase inhibitor as a dual-functional nano-radiosensitizer for enhanced radiotherapy of breast cancer

“…As the first FDA approved HDAC inhibitor, SAHA is used for the treatment of cutaneous T-cell lymphoma and undergoes clinical trials for breast cancer, small cell lung cancer, etc. (Grant et al., 2007 ; Sankar et al., 2015 ; Zeng et al., 2016 ; Rodriguez et al., 2020 ; Lu et al., 2021 ). The side effects of SAHA, such as allergic reaction, cardiac toxicity, and diarrhea, poor water solubility induced by the highly non-polar nature of SAHA, and poor tumor targeting ability, however, limit its clinical efficacy (Cai et al., 2010 ; Duvic & Dimopoulos, 2016 ; Kaur et al., 2021 ).…”

Epigenetic Modification of PD-1/PD-L1-Mediated Cancer Immunotherapy against Melanoma

“…HDAC inhibitor reactivates exhausted T cells via the alteration of the epigenetic modification. A diethylenetriamine-vorinostat encapsulated siRNA-PD-L1 drug delivery system was developed [71], and the vorinostat-loaded vesicle exhibited a high efficacy in inducing a cytotoxic reaction and apoptosis in the tumor cells in vivo [71].…”