Development of a novel morphological paclitaxel-loaded PLGA microspheres for effective cancer therapy: in vitro and in vivo evaluations

Zongrui Zhang,Xinyu Wang,Binbin Li,Yuanjing Hou,Jing Yang,Li Yi

doi:10.1080/10717544.2017.1422296

Abstract

Sustained release of therapeutic agents into tumor cells is a potential approach to improve therapeutic efficacy, decrease side effects, and the drug administration frequency. Herein, we used the modified double-emulsion solvent evaporation (DSE) method to prepare a novel morphological paclitaxel (PTX) loaded poly(lactide-co-glycolide) (PLGA) microspheres (MS). The prepared rough PTX-PLGA-MS possessed microporous surface and highly porous internal structures, which significantly influenced the drug entrapment and release behaviors. The rough MS with an average particle size of 53.47 ± 2.87 μm achieved high drug loading (15.63%) and encapsulation efficiency (92.82%), and provided a favorable sustained drug release. The in vitro antitumor tests of flow cytometry and fluoroimmunoassay revealed that the rough PTX-PLGA-MS displayed effective anti-gliomas activity and enhanced the cellular PTX uptake through adsorptive endocytosis. Both in vitro and in vivo antitumor results demonstrated that the sustained-release PTX could induce the microtubules assembly and the over-expression of Bax and Cyclin B1 proteins, resulting in the microtubule dynamics disruption, G2/M phase arrest, and cell apoptosis accordingly. Furthermore, as the rough PTX-PLGA-MS could disperse and adhere throughout the tumor sites and cause extensive tumor cell apoptosis with one therapeutic course (12 days), they could reduce the system toxicity and drug administration frequency, thus achieving significant tumor inhibitory effects with rapid sustained drug release. In conclusion, our results verified that the rough PTX-PLGA-MS drug release system could serve as a promising treatment to malignant glioma.

Highlights

Glioma is the most aggressive and frequent common intracranial malignant tumor, comprising approximately 50% of all intracranial tumors and causing cancer-related death worldwide (Yang & Wang, 2016; Wang et al, 2017)
The rough PTXPLGA-MS prepared with a higher external PVA concentration showed a homogeneous internal porous structure and micropores surface with deep surface folds compared to that of smooth MS
The current study developed rough PTX-PLGA-MS with microporous surface and internal porous structures to achieve these advantages

Summary

Introduction

Glioma is the most aggressive and frequent common intracranial malignant tumor, comprising approximately 50% of all intracranial tumors and causing cancer-related death worldwide (Yang & Wang, 2016; Wang et al, 2017). The successful treatments are still remarkably limited by the conventional chemotherapy resistance and the frequency of drug use (Guo et al, 2011; Floyd et al, 2016). The development of novel strategies to achieve effective chemotherapy becomes essential in the treatment of malignant glioma. Paclitaxel (PTX) as a new class of microtubule stabilizing agent, has shown significant antitumor efficacy against various tumors, including refractory ovarian, breast, lung, and other cancer types (Hou et al, 2017; Yu et al, 2017). Its successful clinical cancer therapy is compromised by its poor aqueous solubility, drug resistance in tumor cells, and nonspecific pharmacokinetics in systemic circulation (Duan et al, 2017). The effective anti-gliomas efficacy of PTX is limited by its poor permeability across the blood-brain barrier (BBB) and the inability to maintain a higher drug concentration at the tumor sites (Zhan et al, 2010)

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