|
Advancements in iron oxide nanoparticles for targeted drug delivery in cholangiocarcinoma and non-viral therapeutic siRNA delivery in leukemia |
|---|---|
| รหัสดีโอไอ | |
| Title | Advancements in iron oxide nanoparticles for targeted drug delivery in cholangiocarcinoma and non-viral therapeutic siRNA delivery in leukemia |
| Creator | Panadda Yotsomnuk |
| Contributor | Wanwisa Skolpap, Advisor |
| Publisher | Thammasat University |
| Publication Year | 2567 |
| Keyword | Superparamagnetic nanoparticles, Cholangiocarcinoma, Drug release, Astilbin, Bovine serum albumin, Polyethyleneimine, siRNA therapy, Leukemia, อนุภาคนาโนเหล็กออกไซด์ซุปเปอร์พาราแม็กเนติก, มะเร็งท่อน้ำดี, การปลดปล่อยยา, แอสทิลบิน, อัลบูมินเซรัมวัว, โพลิเอทิลีนอิมีน, siRNA บำบัด, มะเร็งเม็ดเลือดขาว |
| Abstract | The research explored two applications of nanotechnology in drug delivery for cancer treatment: drug controlled release and targeted delivery systems. The first aspect focused on the controlled release of drugs using prepared nanoparticles. Specifically, the study analyzed the in vitro drug release kinetics of astilbin (AST)-loaded lauric acid (LA)/bovine serum albumin (BSA)-coated superparamagnetic iron oxide nanoparticles (SPIONLA/BSA) for cholangiocarcinoma (CCA) therapy. The study aimed to determine the diffusion coefficient (D) and dissolution rate (k'a) of AST, and to assess its in vitro cytotoxicity against KKU-055 and KKU-213 cell lines. The physicochemical properties of BSA and LA-loaded superparamagnetic Fe3O4 nanoparticle (SPIONBSA/LA) were characterized using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), and vibrating-sampling magnetometry (VSM). The in vitro drug release profiles of AST-loaded SPIONLA/BSA demonstrated potential for a pH-sensitive delivery mechanism. The AST release profile at different concentrations (10, 15, 20, and 25 ppm) was best fitted by the Korsmeyer-Peppas model. The release exponents (n ≤ 0.45) indicated that the drug release mechanism was controlled by quasi-Fickian diffusion. The dynamics of AST release, predicted using a combination of the Noyes−Whitney and Fick’s second law, were best modeled by a second order release-rate diffusion control at a 10 ppm loading concentration. In contrast, the higher initial concentration of 20 ppm was best followed a first order release-rate diffusion control model. In the cytotoxicity studies, SPIONLA/BSA demonstrated a dose-dependent reduction in cell viability (0-150 μg·cm-3), showing greater cytotoxicity compared to uncoated SPION. After 48 h of treatment, the highest cell growth inhibition of cell growth was observed in KKU-213 cells, with a 54.73% reduction in viability. These findings suggest that AST effectively suppresses CCA cell proliferation and that SPIONLA/BSA holds promise as a carrier for anticancer drug delivery.The second aspect of the research focused on nano-targeted delivery systems utilizing small interfering RNA (siRNA) for acute myeloid leukemia (AML) therapy. The siRNA molecules were designed to target specific proteins, thereby suppressing abnormal cell proliferation. We investigated the delivery of siRNA to AML MOLM-13 cells using two lipid-substituted polyethyleneimines (PEIs): a commercially available reagent (Prime-Fect) and a novel reagent with improved lipid substitution (PEI1.2k-PHPA-Lin9). The siRNAs were specifically directed against the oncogenes FLT3 and KMT2A::MLLT3. Both lipopolymer-siRNA complexes has comparable sizes (210-220 nm) and positive ζ-potentials (17 to 25 mV). Although the binding efficiencies of both lipopolymers to siRNA were similar, PEI1.2k-PHPA-Lin9 complexes demonstrated greater resistance to heparin-induced dissociation. Quantitative analysis of gene silencing performed using qPCR and confirmed through immunostaining/flow cytometry, revealed a significant reduction in FLT3 gene expression and protein levels following specific siRNA delivery. Both FLT3 and KMT2A::MLLT3 siRNAs effectively inhibited cell growth, with their combination producing a more potent effect in cell growth and colony formation assays. Apoptosis induction was confirmed via the Annexin V assay after siRNA treatment. Using Luc(+) MOLM-13 cells, the xenografted cell growth was significantly inhibited when FLT3 siRNA was delivered with Prime-Fect delivery, whereas delivery using PEI1.2k-PHPA-Lin9 was less effective. These findings highlight the potential of tailored lipopolymers for implementing RNAi through siRNA delivery to inhibit leukemia growth and support the feasibility of targeting multiple oncogenes as an effective therapeutic strategy. |
