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Methotrexate-Loaded Surface-Modified Solid Lipid Nanoparticles Targeting Cancer Expressing COX-2 Enzyme
Swagata Patra1, Joykrishna Dey1, Somnath Kar2
1Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India.
Abstract:
Cancer is a major public health problem worldwide, and it is the second leading cause of death of humans in the world. The present study has been directed toward the preparation of methotrexate-loaded surface-modified solid lipid nanoparticles (SLNs) for potential use as a chemotherapeutic formulation for cancer therapy. A lipid (C14-AAP) derived from myristic acid (C14H30O2) and acetaminophen (AAP) was employed as a targeting ligand for human breast and lung cancer cells that overexpress the cyclooxygenases-2 (COX-2) enzyme. The SLNs consisting of stearic acid and C14-AAP were characterized by several methods, including dynamic light scattering (DLS), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), ultraviolet-visible (UV-vis) spectroscopy, high-resolution transmission electron microscopy (HRTEM), and field emission scanning electron microscopy (FESEM) techniques. An in vitro cell cytotoxicity study was done by carrying out an MTT assay and flow cytometry study in the human breast cancer (MCF7) and human lung cancer cell line (A549). The expression level of COX-2 enzyme in MCF7 and A549 cell lines was examined by reverse transcription polymerase chain reaction (RT-PCR). A high level of COX-2 expression was observed in both cell lines. In vitro cell cytotoxicity study in MC7 and A549 cell lines showed the surface-modified, methotrexate-loaded SLN is more effective in cell killing and induction of apoptotic death in both the cell lines than free methotrexate in MTT, flow cytometry, clonogenic assay, and Western blot studies. The surface-modified SLN was radiolabeled with 99mTc with %RCP greater than 95%. In vivo biodistribution study of the 99mTc-labeled SLN in melanoma tumor-bearing C57BL6 mice showed moderate tumor uptake of the radiotracer at 3 h post injection. The SPECT/CT image aligns with the biodistribution results. This study shows that AAP-modified SLNs could be a potential chemotherapeutic formulation for cancer therapy.
Insights
Surface-modified solid lipid nanoparticles (SLNs) loaded with methotrexate show enhanced cancer cell killing. These targeted nanoparticles, utilizing a lipid targeting cyclooxygenase-2 (COX-2), offer a promising new approach for cancer therapy.
Area of Science:
- Nanotechnology
- Materials Science
- Biomedical Engineering
Background:
- Cancer is a leading global cause of death, necessitating novel therapeutic strategies.
- Targeting cancer cells overexpressing cyclooxygenase-2 (COX-2) is a key strategy in developing effective treatments.
- Solid lipid nanoparticles (SLNs) offer a promising platform for drug delivery in cancer therapy.
Purpose of the Study:
- To develop and characterize methotrexate-loaded, surface-modified SLNs using a novel lipid (C14-AAP) for targeted cancer therapy.
- To evaluate the in vitro and in vivo efficacy of these targeted SLNs against human breast (MCF7) and lung (A549) cancer cells.
- To assess the potential of AAP-modified SLNs as a chemotherapeutic formulation.
Main Methods:
- Preparation and characterization of C14-AAP modified SLNs using DLS, DSC, PXRD, UV-vis, HRTEM, and FESEM.
- In vitro cytotoxicity assessment via MTT assay, flow cytometry, and clonogenic assays on MCF7 and A549 cell lines.
- RT-PCR for COX-2 expression analysis, radiolabeling with 99mTc, and in vivo biodistribution studies in mice using SPECT/CT imaging.
Main Results:
- High COX-2 expression was confirmed in both MCF7 and A549 cancer cell lines.
- Methotrexate-loaded, AAP-modified SLNs demonstrated superior efficacy in cell killing and apoptosis induction compared to free methotrexate.
- Radiolabeled SLNs showed good stability (%RCP > 95%) and moderate tumor uptake in vivo, correlating with SPECT/CT imaging.
Conclusions:
- C14-AAP modified SLNs effectively target COX-2 overexpressing cancer cells.
- Surface-modified SLNs loaded with methotrexate represent a potent chemotherapeutic formulation with enhanced efficacy.
- This targeted nanoparticle approach holds significant potential for advancing cancer therapy.
