Treatment of Melanoma by Nano-conjugate-Delivered Wee1 siRNA

Abstract

Small interfering RNA (siRNA)-based drugs have shown tremendous potential to date in cancer gene therapy. Despite the considerable efforts in siRNA design and manufacturing, unsatisfactory delivery systems persist as a limitation for the application of siRNA-based drugs. In this work, the cholesterol, cell-penetrating peptide conjugate cRGD (R8–cRGD), and polyethylene glycol (PEG) were introduced into low-molecular-weight polyethyleneimine (LMW PEI) to form cRGD–R9–cholesterol–PEI–PEG (RRCPP) nanoparticles with specific targeting and highly penetrating abilities. The enhanced siRNA uptake efficiency of the RRCPP delivery system benefited from R8–cRGD modification. Wee1 is an oncogenic nuclear kinase that can regulate the cell cycle as a crucial G2/M checkpoint. Overexpression of Wee1 in melanoma may lead to a poor prognosis. In the present study, RRCPP nanoparticles were designed for Wee1 siRNA delivery to form an RRCPP/siWee1 complex, which significantly silenced the expression of the WEE1 gene (>60% inhibition) and induced B16 tumor cell apoptosis by abrogating the G2M checkpoint and DNA damage in vitro. Furthermore, the RRCPP/siWee1 complex suppressed B16 tumor growth in a subcutaneous xenograft model (nearly 85% inhibition rate) and lung metastasis (nearly 66% inhibition rate) with ideal in vivo safety. Briefly, our results support the validity of RRCPP as a potential Wee1 siRNA carrier for melanoma gene therapy.

Advances in Nonviral mRNA Delivery Materials and Their Application as Vaccines for Melanoma Therapy

“…Future work could also focus on using other types of RNA to treat melanoma. Several studies have already investigated the antitumor efficacy of short interfering RNA (siRNA) in melanoma models. − Many of these siRNA therapies utilize the nonviral carriers discussed in this review. From a manufacturing and development standpoint, this is a major advantage because the same delivery materials can be used to efficiently deliver multiple types of nucleic acid cargo.…”

Single Micelle Vectors based on Lipid/Block Copolymer Compositions as mRNA Formulations for Efficient Cancer Immunogene Therapy

“…To test the therapeutic effect and safety of the DMP/mIL-22BP complex, female BALB/c mice (6–8 weeks) were intravenously injected with 3 × 10 5 cells and then randomly divided into four groups. , On day 3, the four groups of mice were intravenously injected with saline, DMP, DMP/Scr (10 μg), or DMP/mIL-22BP (10 μg). Treatments were performed daily for 11 days.…”

The role of cell‐penetrating peptides in potential anti‐cancer therapy

“…The system consists of the CPP (R8), cholesterol, PEG and cyclic RGD that binds to the integrin αvβ3 receptor. The results showed that the RRCPP/si WEE1 complex loaded with WEE1 siRNA drugs could significantly inhibit tumour growth in melanoma cancer models with high stability and feasibility 105 …”