Abstract
Cancer is associated with single or multiple gene defects. Recently, much research has focused on incorporating genetic materials as one of the means to treat various types of carcinomas. RNA interference (RNAi) conveys an alternative genetic approach for cancer patients, especially when conventional medications fail. RNAi involves the inhibition of expression of specific messenger RNA that signals for uncontrollable cell growth and proliferation, most notably with carcinoma cells. This molecular technology is promising as genetic materials allow us to overcome issues associated with chemotherapeutic agents including organ damage associated with severe drug toxicities. Nonetheless, vast challenges impede successful gene therapy application, including low tumor localization, low stability and rapid clearance from the blood circulation. Owing to the limited treatment opportunities for the management of cancer, the development of effective siRNA carrier systems involving nanotherapeutics has been extensively explored. Over the past years, several siRNA nanotherapeutics have undergone a period of clinical investigation, with some demonstrating promising antitumor activities and safety profiles. Extensive observation of siRNA-nanoparticles is necessary to ensure commercial success. Therefore, this review mainly focuses on the progress of siRNAs-loaded nanoparticles that have undergone clinical trials for cancer treatment. The status of the siRNA nanotherapeutics is discussed, allowing comprehensive understanding of their gene-mediated therapeutics.
Highlights
RNA interference (RNAi) is an innovative approach based on the delivery of noncoding double-stranded RNA into cancer cells to trigger a homology-dependent degradation of the targeted messenger RNA, leading to a selective and specific gene silencing [1,2]
Phase I trials have commenced for all siRNA anticancer nanotherapeutics: Phase I trials of CALAA-01 and DCR-MYC on patients with solid tumor, multiple myeloma and myeloma were terminated due to dose-limiting toxicities and sponsor decisions
A pre-clinical study performed on a KRAS mutant non-small-cell lung cancer (NSCLC) xenograft model receiving NBF-006 showed that NBF-006 was well tolerated by the animal models; 70–80% of the administered dose was internalized by the tumor tissues, causing significant tumor suppression and prolonged survival [59]
Summary
RNA interference (RNAi) is an innovative approach based on the delivery of noncoding double-stranded RNA (dsRNA) into cancer cells to trigger a homology-dependent degradation of the targeted messenger RNA (mRNA), leading to a selective and specific gene silencing [1,2]. The small dimension conjugated application siRNA-based nanotherapies in treating a wide variety tumors allows Clinical localization and of distribution into its molecular targets within the ofcell, which in poses numerous advantages;. Clinical of siRNA-based in [19,20]; treating wide variety profiles withapplication minimal off-target effects andnanotherapies immunogenicity (3)a various siRNA of tumors poses numerous (1) siRNA nanotherapeutics cansuppression selectivelyeffect and preftherapeutics exhibited advantages;. More than twenty years, huge advancement siRNA technology was accomvariousFor therapeutics exhibited a promising in antiproliferative and tumor growth plished; stable chemically modified moieties were constructed, and a wide variety suppression effect in vitro through the stat pathway and PLK1 [21,22], suppression of of novel nanodelivery systems were acquired. For more than twenty years, huge advancement in siRNA technology was accomplished; stable chemically modified siRNA moieties were constructed, and a wide variety which were initiated in 2012 and, to date, several synthetic siRNA-based therapeutics have been studied to treat recurrent and aggressive tumors, which are discussed in this review
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