Abstract
Hyperactivity of signal transducer and activity of transcription 3 (STAT3) plays a crucial role in melanoma invasion and metastasis. Gene therapy applying siRNA targeting STAT3 is a potential therapeutic strategy for melanoma. In this article, we first fabricated safe and novel dissolving microneedles (MNs) for topical application of STAT3 siRNA to enhance the skin penetration of siRNA and used polyethylenimine (PEI, 25 kDa) as carrier to improve cellular uptake of siRNA. The results showed that MNs can effectively penetrate skin and rapidly dissolve in the skin. In vitro B16F10 cell experiments presented that STAT3 siRNA PEI complex can enhance cellular uptake and transfection of siRNA, correspondingly enhance gene silencing efficiency and inhibit tumor cells growth. In vivo experiments indicated that topical application of STAT3 siRNA PEI complex delivered by dissolving MNs into skin can effectively suppress the development of melanoma through silencing STAT3 gene, and the inhibition effect is dose-dependent. STAT3 siRNA delivery via dissolving MNs is a promising approach for skin melanoma treatment with targeting inhibition efficacy and minimal adverse effects.
Highlights
Melanoma, a severe malignant tumor, initiates in melanocytes[1]
The results indicate that signal transducer and activity of transcription 3 (STAT3) Small interfering RNA (siRNA) can silence STAT3 gene of B16F10 cells, it must be first transferred into B16F10 cells via carrier, and PEI is an effective vehicle for transferring STAT3 siRNA into tumor cells
STAT3 is hyperactive in melanoma, its abnormal activation promotes tumor cell proliferation, suppresses apoptosis, and induces invasion and metastasis; silencing STAT3 gene by siRNA is a promising strategy for treating melanoma[50,51]
Summary
A severe malignant tumor, initiates in melanocytes[1]. It leads to ~75% deaths associated with skin cancer[2]. The activation of STAT3 can increase the code of apoptosis inhibition genes Bcl-xl, Bcl-2, Mcl-1, and survivin[14], and improve the expression of cell cycle regulatory cyclin D1 and myc[15,16]. Microneedles (MNs) have been shown to overcome SC barrier, penetrate the skin and into the viable epidermis or dermis in a minimally invasive manner[29], and they have been used for the delivery of macromolecules including human growth hormone[30], interferon-α-2b31, hepatitis B surface antigen[32], insulin[33,34,35], anti-PD1 antibody[36], and siRNA37,38. We hypothesized that STAT3 siRNA could effectively be delivered via MNs to the deep layer of skin, readily accumulate in the local tumor, targetedly silence STAT3 gene, and directly inhibit the melanoma development without leakage into the systemic circulation for reducing the toxicity. The cellular uptake, anti-proliferation, and gene silencing efficiency of STAT3 siRNA PEI complex (PEI/siRNA) were observed with B16F10 melanoma cells in vitro, and the anti-melanoma activity of PEI/siRNA delivered by dissolving MNs was evaluated with mouse melanoma in vivo
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