DNA repair enzyme regulation strategy for enhanced pancreatic neuroendocrine tumour therapy via targeting siRNA-lipid nanoparticles

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Introduction: Pancreatic neuroendocrine tumours (panNETs) originate from neuroendocrine cells with high rates of metastasis, rendering many patients’ ineligible for surgical resection. The first-line chemotherapeutic agent temozolomide (TMZ) for metastatic panNETs faces challenges related to resistance, primarily mediated by the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT).

Aim(s): We hope to introduce the DNA repair enzyme inhibition strategy to not only benefit solving the clinical problem of panNET treatment, but also enlighten the research field to introduce the RNA therapeutics to resolve the problems of clinical used drugs. We designed the octreotide-modified Lipid nanoparticles (LNPs)which also encapsulated the TMZ and MGMT siRNA simultaneously to realise:1) the LNPs could protect the siRNA from degradation and simultaneously encapsulate TMZ for enhanced therapy; 2) the octreotide could specifically target the SSTR of panNET to improve the delivery efficacy; 3) the MGMT siRNA would inhibit the MGMT, not only largely enhance the TMZ efficacy but inhibit its resistance.

Materials and methods: We developed the LNPs modified with Octreotide to co-deliver the TMZ and MGMT-siRNA (LOTR) to improve the therapeutic efficacy of TMZ via inhibiting MGMT-mediated resistance and also reducing systemic toxicity caused by TMZ.

Conference:

Presenting Author: Wang F

Authors: Wang F, Xu J, Xu X, Qin Y, Chen J,

Keywords: Lipid nanoparticle, siRNA, DNA repair enzyme, pancreatic neuroendocrine tumour, temozolomide,