Design of a Multifunctional Smart Polymeric Drug Delivery System Radiolabeling and Investigation of in vitro Biological Properties

Project no. 22255 · Status: Kapanmış (Yayın bekleniyor) · 2021

Summary

This study reports a dual-drug therapeutic system developed using targeted polymeric nanoparticles containing a combination of thymoquinone (TQ) extracted from Nigella sativa L. (black seed) and doxorubicin (DOX). TQ has been demonstrated to overcome drug resistance and protect healthy tissues, while DOX is a widely used chemotherapeutic agent that specifically targets neoplastic cells. Polymeric nanoparticles enhance the stability of drug and improve targeted delivery, significantly improving therapeutic efficacy through targeting strategies.In this study, folate molecules were utilized as active targeting agents, as they can bind to folate receptors, which are overexpressed in cancer cells. Folate was conjugated to NH₂-PEG-b-PCL to facilitate effective targeting of cancer cells. Additionally, the synthesis of the pyrazole (Pz) chelate formed an essential part of this thesis. The pyrazole group was first protected with a BOC group, and then the Pz(BOC) compound was conjugated with the NH₂-PEG-b-PCL polymer. Afterward, the BOC group was removed under acidic conditions, resulting in the formation of Pz-NH₂-PEG-b-PCL complex.The NH₂-PEG-b-PCL complex was conjugated with folic acid, and subsequently, folate-NH₂-PEG-b-PCL, Pz-NH₂-PEG-b-PCL, and drug-loaded (TQ and DOX) polymeric micelles were formed to create functionalized nanoparticles (FNPs). Quality control of the generated structures was performed through Dynamic Light Scattering (DLS), Scanning Electron Microscopy (SEM), and Nuclear Magnetic Resonance (NMR) techniques. Drug loading efficiency was determined by High-Performance Liquid Chromatography (HPLC), confirming the suitability of the drug loading capacity.The system was radiolabeled with 99mTc tricarbonyl ([99mTc(CO)₃]⁺), and it was observed that the pyrazole-based chelate provided higher radiolabeling efficiency compared to nanoparticles without the chelate. This finding indicates that the pyrazole chelate showed superior performance in the radiolabeling process.Biological activity assessments were conducted on MCF-7 and MDA-MB-231 breast adenocarcinoma cell lines, with high cytotoxicity observed at low concentrations in MDA-MB-231 cells. In the incorporation study, the binding efficiencies of radiolabeled compounds to the cell lines were investigated. It was found that [99mTc(CO)₃]⁺ radiolabeled FNPs had higher binding efficiency to MDA-MB-231 cells compared to non-chelated nanoparticles. Moreover, apoptosis assays indicated that FNPs administered at lower doses in the MDA-MB-231 cell line induced significantly higher cell death and triggered apoptotic processes compared to the MCF-7 cell line. This suggests that even at lower concentrations, the system holds promising therapeutic potential.

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