PH-Sensitive Mixed Micelles Assembled from PDEAEMA-PPEGMA and PCL-PPEGMA for Doxorubicin Delivery: Experimental and DPD Simulations Study.

Chufen Yang,Shengqiu Tang,Yaoxi Chen,Wenyao Liu,Jianwei Guo,Cong Yuan,Jiayu Xiao,Hangbo Yue,Dongyu Zhu,Xiaoying Dong,Wenjing Lin

doi:10.3390/pharmaceutics12020170

Abstract

To decrease critical micelle concentration (CMC), improve stability, and keep high drug-loading capacity, three pH-sensitive mixed micelles applied for anticancer drug controlled delivery were prepared by the mixture of polymers poly (N,N-diethylaminoethyl methacrylate)-b-poly(poly(ethylene glycol) methyl ether methacrylate) (PDEAEMA-PPEGMA) and polycaprolactone-b-poly (poly(ethylene glycol) methyl ether methacrylate) (PCL-PPEGMA), which were synthesized and confirmed by 1H NMR and gel permeation chromatographic (GPC). The critical micelle concentration (CMC) values of the prepared mixed micelles were low, and the micellar sizes and zeta potentials of the blank mixed micelles demonstrated good pH-responsive behavior. Combined experimental techniques with dissipative particle dynamics (DPD) simulation, the particle sizes, zeta potentials, drug loading content (LC), encapsulation efficiency (EE), aggregation morphologies, and doxorubicin (DOX) distribution of the mixed micelles were investigated, and the high DOX-loading capacity of the mixed micelles was found. Both in vitro DOX release profiles and DPD simulations of the DOX dynamics release process exhibited less leakage and good stability in neutral conditions and accelerated drug release behavior with a little initial burst in slightly acidic conditions. Cytotoxicity tests showed that the polymer PDEAEMA-PPEGMA and the blank mixed micelles had good biocompatibility, and DOX-loaded mixed micelles revealed certain cytotoxicity. These results suggest that the drug-loaded mixed micelles that consisted of the two polymers PDEAEMA-PPEGMA and PCL-PPEGMA can be new types of pH-responsive well-controlled release anticancer drug delivery mixed micelles.

Highlights

In recent years, nanoscopic polymeric micelles self-assembled by amphiphilic polymers have emerged as prospective nanocarriers for drug delivery, which show unique advantages in enhancing drug bioavailability, improving therapeutic efficacy, and lowering side effects [1,2,3,4,5]
The PDEAEMA-PPEGMA and PCL-PPEGMA polymers were synthesized and confirmed by 1H NMR and gel permeation chromatographic (GPC), and their self-assembled mixed micelles were applied for the delivery of anticancer drug
The micellar sizes and zeta potentials of the blank mixed micelles were all dependent on the pH values obviously, indicating that mixed micelles formed from the mixture of PDEAEMA-PPEGMA and PCL-PPEGMA had good pH-responsive behavior

Summary

Introduction

Nanoscopic polymeric micelles self-assembled by amphiphilic polymers have emerged as prospective nanocarriers for drug delivery, which show unique advantages in enhancing drug bioavailability, improving therapeutic efficacy, and lowering side effects [1,2,3,4,5]. These typical polymeric micelles have a core–shell structure because a hydrophobic inner core can encapsulate hydrophobic drugs, and the outer hydrophilic shell keeps the system stable in the long-time circulation and decreases the toxicity of drugs in the human body [6,7,8,9]. In Leroux’s work, the mixed block polymeric micelles composed of poly(ethylene glycol)-b-poly(D-lactide) (PEG-PDLA) and poly(ethylene glycol)-b-poly(L-lactide) (PEG-PLLA) showed better performance [good drug loading content (LC), great encapsulation efficiency (EE), and well-controlled release rates] than either of the polymers alone [25]

Methods

Results

Conclusion