Abstract
Cutaneous melanoma is the most aggressive skin cancer with notorious drug resistance. Inhibition of immune checkpoint molecules is one of the most promising approaches for cancer therapy. Herein, we show that RNAi mediated silencing of STAT3 expression in the tumor tissue robustly inhibit tumor growth in B16F10 mouse model of melanoma. We designed a peptidomimetic-based lipid nanoparticles (LNPs) for the delivery of siRNA in mouse model of melanoma. When systemically administered, the novel formulation (denote DoCh) preferentially delivered siRNA to the tumor tissue. Remarkably, sequential intravenous injections of siRNA against STAT3 induced profound silencing of STAT3 expression in tumor tissue, which resulted in significant downregulation of PD-L1, leading to significant inhibition of tumor growth through inhibition of tumor immune checkpoint. Moreover, DoCh-mediated siRNA delivery did not show noticeable damage to the major organs. Collectively, our data demonstrated that DoCh LNP is a promising tumor-targeted siRNA delivery system.
Highlights
Cutaneous melanoma is the most aggressive skin cancer which has high plasticity and drug resistance
Chemotherapy is often ineffective for advanced malignant melanoma because of the intrinsic or extrinsic drug resistance of the cancer cells, which results, in part, from an altered apoptotic pathway following overexpression of Bcl-2 that reduces the response to anticancer agents [4]
BRAF is activated by somatic point mutation in human cancer [5,6]
Summary
Cutaneous melanoma is the most aggressive skin cancer which has high plasticity and drug resistance. SiBRAF has been delivered to basal epidermis using edge-activated liposomes for melanoma therapy [11] Another promising target for melanoma therapy is signal transducer and activator of transcription 3 (STAT3), which has an important role in tumor cell proliferation, survival, invasion and immunosuppression [12]. SiRNA against STAT3 has been delivered to melanoma cells through lipid conjugated PEI [13], via dissolving microneedles [14] and gold nanoparticles [15], resulting in decreased STAT3 activity leading to the enhanced cancer cell apoptosis, decreased VEGF level and inhibition of tumor growth. For the first time in our knowledge, that systemic administration of siRNA against STAT3 complexed to DoCh LNP to B16F10 mouse melanoma model resulted in accumulation of the siRNA in tumor tissue, remarkably downregulated the expression STAT3 and the downstream gene PD-L1, and inhibited tumor growth possibly through partial elimination of immune checkpoint. Our data suggests that DoCh LNP is a promising siRNA carrier system for tumor-targeted RNAi therapy
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