Abstract
The power of tumorigenesis, chemo-resistance and metastasis in malignant ovarian tumors resides in a tiny population of cancer cells known as ovarian cancer stem cells (OCSCs). Developing nano-therapeutic targeting of OCSCs is considered a great challenge. The potential use of poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) was investigated as a drug delivery system for paclitaxel (PTX) against OCSCs in vitro and in vivo. PTX-loaded PLGA NPs were prepared by an emulsion solvent evaporation method, supported by incorporation of folic acid (FA) as the ligand. NPs were characterized for size, surface morphology, drug loading, and encapsulation efficiency. In vitro cytotoxicity of PTX-loaded FA/PLGA NPs was tested against OCSCs with MTT assay. In vivo anti-tumoral efficiency and active targeting potential of prepared NPs against tumors in nude mice were investigated. In vitro results revealed that IC50 of PTX was significantly reduced after loading on PLGA NPs. On the other hand, in vivo results showed that PLGA NPs enhanced the tumor suppression efficiency of PTX. Investigation with real time quantitative PCR analysis revealed the limiting expression of chemo-resistant genes (ABCG2 and MDR1) after applying PLGA NPs as a drug delivery system for PTX. Histopathological examination of tumors showed the effective biological influence of PTX-loaded FA/PLGA NPs through the appearance of reactive lymphoid follicles. Targeting potential of PTX was activated by FA/PLGA NPs through significant preservation of body weight (p < 0.0001) and minimizing the systemic toxicity in healthy tissues. Immunohistochemical investigation revealed a high expression of apoptotic markers in tumor tissue, supporting the targeting effect of FA/PLGA NPs. A drug delivery system based on FA/PLGA NPs can enhance PTX’s in vitro cytotoxicity and in vivo targeting potential against OCSCs.
Highlights
Ovarian cancer is one of the most lethal types of gynecologic malignancy [1]
Ovarian cancer stem cells (OCSCs) are a small subpopulation of ovarian cancer cells that are capable of self-renewal and differentiation into multiple ovarian malignant cell types
Due to the presence of efflux mechanisms, by increasing expression of defense factors involved in reducing intra-cellular drug dose such as ATP binding cassette (ABC) and multi-drug resistance (MDR) transporters, CSCs are resistant to the current chemotherapy compared to non-tumorigenic cells [6]
Summary
Ovarian cancer is one of the most lethal types of gynecologic malignancy [1]. Ovarian cancer stem cells (OCSCs) are a small subpopulation of ovarian cancer cells that are capable of self-renewal and differentiation into multiple ovarian malignant cell types. The ovarian cancer cells that express CD44+ exhibit cancer stem cell-like properties of migration and chemo-resistance. Paclitaxel (PTX) is a standard chemo-drug against ovarian tumors. The other obstacle in ovarian cancer therapy is the difficulty of targeting the CSCs’ subpopulation in ovarian tumors using traditional drug carriers [4]. CSCs stimulate effective chemo-drug resistance pathways that pump the toxic drugs out of the cells [5]. Nanotechnology may represent a promising drug delivery system (DDS) that can safely target OCSCs within malignant ovarian tumors [7]
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