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Delivery of Small Interfering RNA with Micelleplex from Polymer Micelles for Cancer Therapy

Author: MaoChengQiong
Tutor: WangJun
School: University of Science and Technology of China
Course: Biological materials
Keywords: cancer therapy micelleplex siRNA synthetic lethality KRAS mutation breast cancer NSCLC drug delivery
CLC: R318.08
Type: PhD thesis
Year: 2013
Downloads: 64
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Abstract

Cancer remains the leading cause of death in the world after heart and infectious diseases. Radiotherapy and chemotherapy are two of the major treatment modalities for cancer, which are accompanied by inevitable side effects. Thus, identifying therapeutics that will kill cancer cells and do not harm patients is the bottleneck, which lies with our inability. Based on the fact that nanoparticulate siRNA delivery system has shown great promise for cancer therapy, the suitable drug target and nanocarrier can be chosen for efficient gene downregulation and tumor growth inhibition. On the other hand, the therapeutics based on RNAi are not omnipotent and a lot of drug targets still undruggable. With a more complete understanding of the complex and extensive network of effectors and regulators, secondary dependencies on genes that are themselves not oncogenes but could lead to vulnerabilities caused by the target genes mutation state can also be developed to provide more efficient and safe therapeutic opportunities.This dissertation aims to exploit safe and efficient treatment against cancer based on siRNA delivery system with micelleplex. The main content and conclusions of this dissertation are summarized as below:1. One of the key challenges in the development of RNA interference-based cancer therapy is the lack of an efficient delivery system for synthetic small interfering RNAs (siRNAs) that would enable efficient uptake by tumor cells and allow for significant knockdown of a target transcriptin vivo. In this part, we have developed a micelleplex system based on an amphiphilic and cationic triblock copolymer, which can systemically deliver siRNA targeting the acid ceramidase (AC) gene for cancer therapy. The triblock copolymer, mPEG-b-PCL-b-PPEEA, can self-assemble into micellar nanoparticles (MNPs) in aqueous solution with an average diameter of60nm and a zeta potential of approximately48mV. The resulting micelleplex, formed by the interaction of MNPs and siRNA, was effectively internalized by BT474breast cancer cells and siRNA was subsequently released, resulting in significant gene knockdown. This effect was demonstrated by significant down-regulation of luciferase expression in BT474-luciferase cells which stably express luciferase, and suppression of AC expression in BT474cells at both the transcriptional and protein level, following delivery of specific siRNAs by the micelleplex. Furthermore, a micelleplex carrying siRNA targeting the AC gene was found to induce remarkable apoptosis and reduce the proliferation of cancer cells. Systemic delivery of micelleplexsiAC significantly inhibited tumor growth in a BT474xenograft murine model, with depressed expression of AC and no positive activation of the innate immune response, suggesting therapeutic promise for micelleplex siRNA delivery in cancer therapy.2. The KRAS mutation is present in approximately20%of lung cancers and has not yet been effectively targeted for therapy. This mutation is associated with a poor prognosis in NSCLC and confers resistance to standard anticancer treatment drugs, including EGFR tyrosine kinase inhibitors. In this part, we have exploited a new therapeutic strategy based on the synthetic lethal interaction between CDK4downregulation and the KRAS mutation to deliver micellar nanoparticles containing siRNA targeting CDK4(MNPsiCDK4) for treatment in NSCLC harboring the oncogenic KRAS mutation. Following MNPSiCDK4administration, CDK4expression was decreased, accompanied by inhibited cell proliferation, specifically in KRAS mutant NSCLC. However, this intervention was harmless to normal KRAS wild-type cells, confirming the proposed mechanism of synthetic lethality. Moreover, systemic delivery of MNPsiCDK4significantly inhibited tumor growth in an A549NSCLC xenograft murine model, with depressed expression of CDK4and mutational KRAS status, suggesting the therapeutic promise of MNPsiCDK4delivery in KRAS mutant NSCLC via a synthetic lethal interaction between KRAS and CDK4. These investigations are promising in terms of exploiting a new therapeutic strategy that is effective and safe in KRAS mutant NSCLC.

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