Encapsulation of chloroquine and doxorubicin by MPEG-PLA to enhance anticancer effects by lysosomes inhibition in ovarian cancer

Abstract

PurposeAs the deadliest gynecological malignancy, ovarian cancer ranks as a major cause of disease-related deaths to women worldwide and is treated with transurethral resection or systemic chemotherapy. However, traditional chemotherapeutic drug in antitumor therapy has shown unavoidable limitations, such as poor curative effects, systemic toxicity and development of drug resistance, leading to failure of tumor inhibition and recurrence. This study aims to explore an innovative method to enhance the clinical efficiency of ovarian cancer.Materials and methodsUsing MTT assay, the cell viability was detected under different culture systems. Western blot was used to examine the expression of P-gp in doxorubicin-resistant and wild-type A2780/SKOV3 cells. We used confocal to examine the drug concentration under different culture conditions. Also, flow cytometry was used to detect the drug absorption at the determined time points under different culture systems. Using nude mice model, we evaluated the killing efficacy of chemotherapeutic drugs with or without nanoparticle encapsulation. ELISA was used to examine the levels of creatinine, alanine aminotransferase and aspartate aminotransferase in plasma.ResultsWe found that pretreatment of chloroquine (CQ) as chemosensitizer markedly enhanced the anticancer effects in ovarian cancer. We also provided evidence that CQ efficiently increase the pH value of lysosomes in tumor cells, leading to the reverse of drug sequestration induced by lysosomes. To further improve the pharmacokinetics profiles and avoid the systemic toxicity caused by chemotherapeutic agents, we encapsulated CQ and chemotherapeutic drugs by polymeric nanoparticles methoxy poly(ethylene glycol)-poly(l-lactic acid). Codelivery of CQ and chemotherapeutic agents by nanocarrier revealed enhanced anticancer effects compared with the free drug delivery by tail vein injection. More importantly, accumulated drugs, prolonged drug circulation and reduced organic damages were observed in nanoparticles delivery.ConclusionCodelivery of CQ and chemotherapeutic drugs by methoxy poly(ethylene glycol)-poly(l-lactic acid) could significantly improve the anticancer effects and might have important potency in clinical applications for ovarian cancer therapy.

Irradiation pretreatment enhances the therapeutic efficacy of platelet-membrane-camouflaged antitumor nanoparticles

“…Lysosome is the intracellular target of some nanomaterials and its permeabilization is involved in material-mediated cell death [35]. Inhibiting lysosome function enhances the antitumor activity of chemotherapeutic drugs and increases the sensitivity of tumors to radiotherapy [36,37]. We employed the acridine orange (AO) dye to stain 4T1 cells.…”

Biocompatibility, biodegradation and biomedical applications of poly(lactic acid)/poly(lactic-co-glycolic acid) micro and nanoparticles

“…Many multifaceted merits are realized in PLA and PLGA based DDS such as sustainment of drug release, targeted delivery, improving the bioavailability, and enhancement of the stability of encapsulated biopharmaceuticals towards enzymatic degradation (Moghimi et al 2001;Mundargi et al 2008). With great effort, in the last years, different PLA and PLGA based drugs delivery systems have been developed, in particular for the delivery of anticancer drugs (Haggag et al 2019;Jain et al 2011Jain et al , 2016Shao et al 2018) and for a specific organ targeting such as brain or liver targeting (Bao et al 2015;Gao et al 2015;Jose et al 2014;Patel et al 2018;Xia et al 2012;Zhu et al 2016). Moreover, these delivery systems have been tested with great results for pulmonary administration of different drugs (Feng et al 2014;Gaspar et al 2019;Takami and Murakami 2011).…”

P2X7R-mediated Autophagic Impairment Contributes to Central Sensitization in a chronic Migraine Model with Recurrent Nitroglycerin Stimulation in Mice

“…An equivalent volume of solvent corresponding to each drug was used as a vehicle control. The drug dosage and methods of delivery were determined by literature data and preliminary experiments [27,[49][50][51][52][53]. All drug solutions were freshly prepared on the day of use.…”