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.
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