Development, characterization and biological in vitro assays of paclitaxel-loaded PCL polymeric nanoparticles (original) (raw)
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A self-assembling nanoparticle for paclitaxel delivery in ovarian cancer
Biomaterials, 2009
Paclitaxel (PTX) is one of the most effective chemotherapeutic drugs for the treatment of a variety of cancers. However, it is associated with serious side effects caused by PTX itself and the Cremophor EL emulsifier. In the present study, we report the development of a well-defined amphiphilic lineardendritic copolymer (named as telodendrimer) composed of polyethylene glycol (PEG), cholic acid (CA, a facial amphiphilic molecule) and lysine, which can form drug-loaded core/shell micelles when mixed with hydrophobic drug, such as PTX, under aqueous condition. We have used PEG 5k -CA 8 , a representive telodendrimer, to prepare paclitaxel-loaded nanoparticles (PTX-PEG 5k -CA 8 NPs) with high loading capacity (7.3 mg PTX/mL) and a size of 20-60 nm. This novel nanoformulation of PTX was found to exhibit similar in vitro cytotoxic activity against ovarian cancer cells as the free drug (Taxol Ò ) or paclitaxel/human serum albumin nanoaggregate (Abraxane Ò ). The maximum tolerated doses (MTDs) of PTX-PEG 5k -CA 8 NPs after single dose and five consecutive daily doses in mice were approximately 75 and 45 mg PTX/kg, respectively, which were 2.5-fold higher than those of Taxol Ò . In both subcutaneous and orthotopic intraperitoneal murine models of ovarian cancer, PTX-PEG 5k -CA 8 NPs achieved superior toxicity profiles and anti-tumor effects compared to Taxol Ò and Abraxane Ò at equivalent PTX doses, which were attributed to their preferential tumor accumulation, and deep penetration into tumor tissue, as confirmed by near infrared fluorescence (NIRF) imaging.
International Journal of Cancer, 2007
The objective of this study was to overcome drug resistance upon systemic administration of combination paclitaxel (PTX) and the apoptotic signaling molecule C 6 -ceramide (CER) in biodegradable poly(ethylene oxide)-modified poly(epsilon-caprolactone (PEO-PCL) nanoparticles. Subcutaneous sensitive (wild-type) and multidrug resistant (MDR-1 positive) SKOV-3 human ovarian adenocarcinoma xenografts were established in female Nu/Nu mice. PTX and CER were administered intravenously either as a single agent or in combination in aqueous solution and in PEO-PCL nanoparticles to the tumor-bearing mice. There was significant (p < 0.05) tumor growth suppression in both wild-type SKOV-3 and multidrug resistant SKOV-3 TR models upon single dose co-administration of PTX (20 mg/kg) and CER (100 mg/kg) in nanoparticle formulations as compared to the individual agents and administration in aqueous solutions. For instance, in SKOV-3 wild-type model, more than 4.3-fold increase (p < 0.05) in tumor growth delay and 3.6-fold (p < 0.05) increase in tumor volume doubling time (DT) were observed with the combination treatment in nanoparticles as compared to untreated animals. Similarly, 3-fold increase (p < 0.05) in tumor growth delay and tumor volume DT was observed in SKOV-3 TR model. Body weight changes and blood cells counts were used as measures of safety and, except for an increase in platelet counts (p < 0.05) in PTX 1 CER treated animals, there was no difference between various treatment strategies. The results of this study show that combination of PTX and CER in biodegradable polymeric nanoparticles can serve as a very effective therapeutic strategy to overcome drug resistance in ovarian cancer. ' 2007 Wiley-Liss, Inc.
International Journal of Pharmaceutics, 2021
Lipid nanocapsules (LNCs) have proven their efficacy in delivering different drugs to various cancers, but no studies have yet described their uptake mechanisms, paclitaxel (PTX) delivery or resulting cytotoxicity towards breast cancer cells. Herein, we report results concerning cellular uptake of LNCs and cytotoxicity studies of PTX-loaded LNCs (LNCs-PTX) on the three breast cancer cell lines MCF-7, MDA-MB-231 and MDA-MB-468. LNCs-PTX of sizes 50 ± 2 nm, 90 ± 3 nm and 120 ± 4 nm were developed by the phase inversion method. Fluorescence microscopy and flow cytometry were used to observe the uptake of fluorescently labeled LNCs and cellular uptake of LNCs-PTX was measured using HPLC analyses of cell samples. These studies revealed a higher uptake of LNCs-PTX in MDA-MB-468 cells than in the other two cell lines. Moreover, free PTX and LNCs-PTX exhibited a similar pattern of toxicity towards each cell line, but MDA-MB-468 cells appeared to be more sensitive than the other two cell lines, as evaluated by the MTT cytotoxicity assay and a cell proliferation assay based upon [ 3 H]thymidine incorporation. Studies with inhibitors of endocytosis indicate that the cellular uptake is mainly via the Cdc42/GRAFdependent endocytosis as well as by macropinocytosis, whereas dynamin-dependent processes are not required. Furthermore, our results indicate that endocytosis of LNCs-PTX is important for the toxic effect on cells. Western blot analysis revealed that LNCs-PTX induce cytotoxicity by means of apoptosis in all the three cell lines. Altogether, the results demonstrate that LNCs-PTX exploit different mechanisms of endocytosis in a cell-type dependent manner, and subsequently induce apoptotic cell death in the breast cancer cells here studied. The article also describes biodistribution studies following intravenous injection of fluorescently labeled LNCs in mice.
Scientific reports, 2018
New therapy development is critically needed for ovarian cancer. We used the chicken egg CAM assay to evaluate efficacy of anticancer drug delivery using recently developed biodegradable PMO (periodic mesoporous organosilica) nanoparticles. Human ovarian cancer cells were transplanted onto the CAM membrane of fertilized eggs, resulting in rapid tumor formation. The tumor closely resembles cancer patient tumor and contains extracellular matrix as well as stromal cells and extensive vasculature. PMO nanoparticles loaded with doxorubicin were injected intravenously into the chicken egg resulting in elimination of the tumor. No significant damage to various organs in the chicken embryo occurred. In contrast, injection of free doxorubicin caused widespread organ damage, even when less amount was administered. The lack of toxic effect of nanoparticle loaded doxorubicin was associated with specific delivery of doxorubicin to the tumor. Furthermore, we observed excellent tumor accumulation ...
Asian Pacific Journal of Cancer Prevention, 2014
Paclitaxel is hydrophobic in nature and is recognized as a highly toxic anticancer drug, showing adverse effects in normal body sites. In this study, we developed a polymeric nano drug carrier for safe delivery of the paclitaxel to the cancer that releases the drug in a sustained manner and reduces side effects. N-isopropylacrylamide/ vinyl pyrrolidone (NIPAAm/VP) nanoparticles were synthesized by radical polymerization. Physicochemical characterization of the polymeric nanoparticles was conducted using dynamic light scattering, transmission electron microscopy, scanning electron microscopy and nuclear magnetic resonance, which confirmedpolymerization of formulated nanoparticles. Drug release was assessed using a spectrophotometer and cell viability assays were carried out on the MCF-7 breast cancer and B16F0 skin cancer cell lines. NIPAAm/ VP nanoparticles demonstrated a size distribution in the 65-108 nm range and surface charge measured-15.4 mV. SEM showed the nanoparticles to be spherical in shape with a slow drug release of ~70% in PBS at 38°C over 96 h. Drug loaded nanoparticles were associated with increased viability of MCF-7 and B16F0 cells in comparison to free paclitaxel. Nano loaded paclitaxel shows high therapeutic efficiency by sustained release action for the longer period of time, i increasing its efficacy and biocompatibility for human cancer therapy. Therefore, paclitaxel loaded (NIPAAm/VP) nanoparticles may provide opportunities to expand delivery of the drug for clinical selection.
Journal of Advanced Zoology, 2023
The effectiveness of paclitaxel as a cancer treatment is widely recognized. However, its solubility issue can be addressed by blending it with ethanol and Cremophor EL, a product marketed under the trade name Taxol. Nevertheless, to enhance the anticancer efficacy of Cremophor EL and reduce adverse effects, alternative delivery methods and strategies must be explored. The objective of this work was to synthesize PLGA nanoparticles (PNF) loaded with paclitaxel and evaluate a number of characteristics, including in vitro drug release, drug loading, polydispersity index, zeta potential, and particle size. Finding the best formulation, PNF4, based on its in vitro drug release properties, was the main goal of the study. The surface morphology of PNF4 was then investigated by means of scanning and transmission electron microscopy after that (SEM and TEM). The delivery method follows the Korsmeyer-Peppas model, according to analysis of the in vitro drug release kinetics, indicating a "Fickian diffusion" mechanism. Furthermore, the in vitro cytotoxicity assessment demonstrated that the PNF4 formulation exhibited superior cytotoxicity compared to free paclitaxel.
International Journal of Nanomedicine, 2012
Background: A multifunctional telodendrimer-based micelle system was characterized for delivery of imaging and chemotherapy agents to mouse tumor xenografts. Previous optical imaging studies demonstrated qualitatively that these classes of nanoparticles, called nanomicelles, preferentially accumulate at tumor sites in mice. The research reported herein describes the detailed quantitative imaging and biodistribution profiling of nanomicelles loaded with a cargo of paclitaxel. Methods: The telodendrimer was covalently labeled with 125 I and the nanomicelles were loaded with 14 C-paclitaxel, which allowed measurement of pharmacokinetics and biodistribution in the mice using microSPECT/CT imaging and liquid scintillation counting, respectively. Results: The radio imaging data showed preferential accumulation of nanomicelles at the tumor site along with a slower clearance rate than paclitaxel formulated in Cremophor EL (Taxol ® ). Liquid scintillation counting confirmed that 14 C-labeled paclitaxel sequestered in nanomicelles had increased uptake by tumor tissue and slower pharmacokinetics than Taxol. Conclusion: Overall, the results indicate that nanomicelle-formulated paclitaxel is a potentially superior formulation compared with Taxol in terms of water solubility, pharmacokinetics, and tumor accumulation, and may be clinically useful for both tumor imaging and improved chemotherapy applications.
Materials Science and Engineering: C, 2019
Ovarian cancer is one of the most lethal gynecologic malignancies due to its rapid proliferation, frequent acquisition of chemoresistance, and widespread metastasis within the peritoneal cavity. Intraperitoneal (IP) chemotherapy has demonstrated significant anti-cancer potential but its broad clinical application is hindered by several drug delivery limitations. Herein, we engineer paclitaxel (PTX) laden hybrid microparticles (PTX-Hyb-MPs) for improved delivery of chemotherapy in ovarian cancer. The PTX-Hyb-MPs are comprised of a lipid-coated shell of poly (lactic acid-co-glycolic acid) (PLGA) encapsulating hydrophobic PTX. A co-axial electrohydrodynamic (CEH) process is used for one-step and scalable production of the PTX-Hyb-MP agent with controlled particles size, uniform size distribution, tunable thickness, and high encapsulation rate (92.17 ± 6.9 %). The multi-layered structure of the PTX-Hyb-MPs is verified by transmission electron microscopy and confocal fluorescence microscopy. The effect of lipid coating on the enhancement of particle interactions with cancer cells is studied by flow cytometry and confocal fluorescence microscopy. The anti-cancer effect of the PTX-Hyb-MPs is evaluated in SKOV-3 ovarian cancer cells in vitro and a cancer xenograft model in vivo, in comparison with conventional drug delivery methods. Our studies reveal that the PTX-Hyb-MP agent can be potentially used for locoregional treatment of ovarian cancer and other tissue malignancies with sustained drug release, tunable release profiles, enhanced drug uptake, and reduced systemic toxicity.
Nanoscale drug delivery strategies for therapy of ovarian cancer: conventional vs targeted
Artificial Cells, Nanomedicine, and Biotechnology
Ovarian cancer is the second most common gynaecological malignancy. It usually occurs in women older than 50 years, and because 75% of cases are diagnosed at stage III or IV it is associated with poor diagnosis. Despite the chemosensitivity of intraperitoneal chemotherapy, the majority of patients is relapsed and eventually dies. In addition to the challenge of early detection, its treatment presents several challenges like the route of administration, resistance to therapy with recurrence and specific targeting of cancer to reduce cytotoxicity and side effects. In ovarian cancer therapy, nanocarriers help overcome problems of poor aqueous solubility of chemotherapeutic drugs and enhance their delivery to the tumour sites either by passive or active targeting, and thus reducing adverse side effects to the healthy tissues. Moreover, the bioavailability to the tumour site is increased by the enhanced permeability and retention (EPR) mechanism. The present review aims to describe the current conventional treatment with special reference to passively and actively targeted drug delivery systems (DDSs) towards specific receptors designed against ovarian cancer to overcome the drawbacks of conventional delivery. Conclusively, targeted nanocarriers would optimise the intra-tumour distribution, followed by drug delivery into the intracellular compartment. These features may contribute to greater therapeutic effect.