Pancreatic neuroendocrine tumors (panNEST) originate from neuroendocrine cells with a high rate of metastasis, making many patients ineligible for surgical resection. The first-line chemotherapeutic drug temozolomide (TMZ), used for metastatic panendocrine disorders, faces challenges of drug resistance, mainly mediated by the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). This resistance limits the long-term efficacy of TMZ in many patients. To overcome these challenges, we developed lipid nanoparticles (LNP) modified with somatostatin receptors (SSTRs), targeting octreotide peptides, and co-delivering TMZ and MGMT-siRNA (LOTR). By inhibiting MGMT-mediated resistance and reducing the systemic toxicity caused by TMZ, the LOTR system enhances the therapeutic effect of TMZ. In vitro and in vivo results indicate that the LOTR system significantly enhances the sensitivity of tumors to TMZ, reduces resistance, and reduces off-target effects, providing a promising approach for the treatment of advanced panNESTs. This study was published in ACS Nano under the title "Regulation Strategy of DNA Repair Enzymes for Enhanced Therapy of Pancreatic Neuroendocrine Tumors via Targeting siRNA-Lipid Nanoparticles".
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DOI: 10.1021/acsnano.5c21452