Development and Characterization of a Copolymeric Micelle Containing Soluble and Insoluble Model Drugs
Farhad Mohammadi, Alireza Moradi, Fatemeh Tavakoli, Samaneh Rahmati, Rashin Giti, Vahid Ramezani
Abstract
Micelles are nano-sized particles with a core-shell structure that are made by natural or synthetic polymers or copolymers. The aim of this study was to develop and characterize a copolymeric micelle using two polymers loaded with hydrophilic and lipophilic drugs.
Introduction
Polymeric micelles are a type of self-assembled nano-carrier that has recently received significant attention in drug delivery due to their low toxicity, improved bioavailability [1], targeted drug delivery, controlled drug release, high drug loading capacity, and enhanced drug solubility. The hydrophilic and hydrophobic blocks of copolymeric micelles form a core-shell nanostructure in aqueous solutions [2–4]. Their amphiphilic properties and capability to form micelles, along with their ability to load hydrophilic and lipophilic drugs, make them suitable for delivering various compounds such as anticancer drugs, proteins, nucleic acids, and contrast/imaging agents [5], as well as antibiotics to overcome antibiotic resistance and enhance therapeutic efficacy [6, 7]. In addition to these advantages, they can be smart and responsive systems to environmental stimulants such as pH, electric and magnetic fields, and ultraviolet waves [8].
Poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) is an FDA-approved biodegradable amphiphilic block copolymer, which has a low critical micelle concentration in aqueous solution (0.014 mg/ml), making it a commonly used for drug delivery [2, 9]. The hydrophilic segment of PEG is a biocompatible and targetable polymer that reduces clearance by the reticuloendothelial system and prolongs circulation time in the blood [10, 11]. On the other hand, the PCL block is a hydrophobic polymer that can serve as the inner core of micelles. It is biocompatible, non-toxic, biodegradable, and ideal for long-lasting drug delivery due to its slow degradation rate [12, 13].
Material and methods
Materials
PCL, PEG (MW = 4000), 4-nitrophenyl chloroformate (NPC), CLM, MFX, pyridine, polyvinyl alcohol (PVA), Tween 80, methanol, and dichloromethane (all from Merck; Massachusetts, USA). Moxifloxacin and clarithromycin (Tehran Chemie; Tehran, Iran). All reagents and solvents were analytical grades.
Methods
High-performance liquid chromatography (HPLC).
Standard serial dilutions of MFX and CLM in phosphate buffer saline were prepared, and 20 μL of each dilution was injected into an HPLC (Young Lin 9100; South Korea) three consecutive times on three different days. A C18 column (150 × 4.6 mm) was used and the mobile phase for CLM and MFX consisted of methanol: monobasic phosphate buffer (13:7) and methanol: buffer (28:72), respectively. The flow rate was set to 1 ml/min and the maximum ultraviolet absorption was read for CLM (210 nm) and MFX (270 nm), respectively [19].
Results
The construction of the copolymer was confirmed by the results of FT-IR and 1H NMR spectroscopy tests. The encapsulation efficiency test exhibited that loading was about 50% for twelve formulations. Particle size, zeta potential, polydispersity index, and transmission electron microscopy confirmed the formation of monodispersed, uniform, and nano-sized micelles with a few negative charges. The kinetic model of release was fitted to the Higuchi model.
Discussion
The EE% ranged from 41.49% to 64.57% for MFX-containing formulations and from 25.41% to 53.03% for CLM-containing formulations. The higher EE% in the MFX indicates that this hydrophilic drug can be loaded on the surface of micelles, which is a considerable area in nanoparticle drug delivery systems. On the contrary, CLM is possibly loaded in the core of micelles. The results of ANOVA showed that the drug/copolymer ratio was another factor that affected EE%, as an increase in the ratio of copolymer enhanced the capacity of micelles to load drugs and consequently increased the EE% (Table 3). Similar results were reported for Clarithromycin by Hadipour Moghaddam et al. [26]. However, ANOVA showed that different emulsifiers had no significant effect on the EE% of micelles in different formulations.
Conclusion
According to the results of this study, polymeric micelles consisting of PEG-PCL copolymer were prepared using the emulsification solvent evaporation method, and the optimized formulations were able to load with adequate concentrations of MFX and CLM. Out of the twelve studied formulations, MT3, MP3, CT3, and CP3 had higher EE%. Their mean particle size was less than 300 nm and thus could penetrate mucous membranes well due to low surface charge. In addition, the release profiles of MFX and CLM from the polymeric micelles were in accordance with the Higuchi model.
Acknowledgments
The present article was extracted from a Pharm D thesis (No. 7369) by Samaneh Rahmati. Appreciation is expressed to Ms. Farzaneh Rasooli for proofreading, copyediting, and improving the English structure of this manuscript.
Citation: Mohammadi F, Moradi A, Tavakoli F, Rahmati S, Giti R, Ramezani V (2023) Development and characterization of a copolymeric micelle containing soluble and insoluble model drugs. PLoS ONE 18(5): e0286251.
https://doi.org/10.1371/journal.pone.0286251
Editor: Lay-Hong Chuah, Monash University Malaysia, MALAYSIA
Received: October 10, 2022; Accepted: May 12, 2023; Published: May 25, 2023
Copyright: © 2023 Mohammadi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting information files.
Funding: This work was financially supported by the Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences and Health Care Services, Yazd, Iran (grant #7369 awarded to F.M.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0286251#abstract0
