Abstract
Pancreatic cancer is one of the most lethal forms of cancer, predicted to be the second leading cause of cancer-associated death by 2025. Despite intensive research for effective treatment strategies and novel anticancer drugs over the past decade, the overall patient survival rate remains low. RNA interference (RNAi) is capable of interfering with expression of specific genes and has emerged as a promising approach for pancreatic cancer because genetic aberrations and dysregulated signaling are the drivers for tumor formation and the stromal barrier to conventional therapy. Despite its therapeutic potential, RNA-based drugs have remaining hurdles such as poor tumor delivery and susceptibility to serum degradation, which could be overcome with the incorporation of nanocarriers for clinical applications. Here we summarize the use of small interfering RNA (siRNA) and microRNA (miRNA) in pancreatic cancer therapy in preclinical reports with approaches for targeting either the tumor or tumor microenvironment (TME) using various types of nanocarriers. In these studies, inhibition of oncogene expression and induction of a tumor suppressive response in cancer cells and surrounding immune cells in TME exhibited a strong anticancer effect in pancreatic cancer models. The review discusses the remaining challenges and prospective strategies suggesting the potential of RNAi-based therapeutics for pancreatic cancer.
Highlights
As an intrinsic mechanism for posttranscription editing, RNA interference (RNAi) comprises two major different types of RNA molecules, small interfering RNA (siRNA), and miRNA, generated via similar mechanisms involving the dicer protein (Figure 1). Both siRNA and miRNA are short non-coding RNA strands that can silence the target messenger RNA (mRNA) in sequence-specific manner, offering the advantage of greater selectivity and expanding the inhibitory action for undruggable targets
Similar to siRNA, miRNA interfere with the expression of specific proteins by binding to organisms as one of the key players in the RNAi machinery as shown in Figure 1 [28]
Chitosan oligosaccharide lactate can be assembled with folic acid and polyethylene glycol into nanoparticles that are capable of encapsulating siRNA and intravenously localizing in tumors in pancreatic orthotopic models [67]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Pancreatic cancer is characterized both by complicated genetic mutations and epigenetic alterations and by development of a dense tumor microenvironment that together result in a low survival rate of just ~15–25% of patients who undergo surgical resection [5]. Undruggable targets represent proteins that is pharmacologically incapable of being targeted due to elusive factors from molecular shapes and mechanism of action For this reason, the potential to selectively inhibit undruggable genes with RNAi represents a promising strategy to halt pancreatic cancer progression. RNAi-based technology has presented an opportunity to regulate a set of tumorpromoting genes in cancer cells and other targets in TME. We discuss the prospects and challenges in RNAi-based approaches using various strategies of nanomedicine to target key genes in cancer cells or TME of pancreatic cancer
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