Π–Π Stacking Increases the Stability and Loading Capacity of Thermosensitive Polymeric Micelles for Chemotherapeutic Drugs

Abstract

Thermosensitive amphiphilic block copolymers self-assemble into micelles above their lower critical solution temperature in water, however, the micelles generally display mediocre physical stability. To stabilize such micelles and increase their loading capacity for chemotherapeutic drugs, block copolymers with novel aromatic monomers were synthesized by free radical polymerization of N-(2-benzoyloxypropyl methacrylamide (HPMAm-Bz) or the corresponding naphthoyl analogue (HPMAm-Nt), with N-(2-hydroxypropyl) methacrylamide monolactate, using a polyethylene glycol based macroinitiator. The critical micelle temperatures and critical micelle concentrations decreased with increasing the HPMAm-Bz/Nt content. The micelles of 30-50 nm were prepared by heating the polymer aqueous solutions from 0 to 50 °C and were colloidally stable for at least 48 h at pH 7.4 and 37 °C. Paclitaxel and docetaxel encapsulation was performed by mixing drug solutions in ethanol with polymer aqueous solutions and heating from 0 to 50 °C. The micelles had a drug loading capacity up to 34 wt % for docetaxel, which is among the highest loadings reported for polymeric micelles, with loaded micelle sizes ranging from 60 to 80 nm. The micelles without aromatic groups almost completely released loaded paclitaxel in 10 days, whereas the HPMAm-Bz/Nt containing micelles released 50% of the paclitaxel at the same time, which showed a better retention for the drug of the latter micelles. (1)H solid-state NMR spectroscopy data are compatible with π-π stacking between aromatic groups. The empty micelles demonstrated good cytocompatibility, and paclitaxel-loaded micelles showed high cytotoxicity to tumor cells. In conclusion, the π-π stacking effect introduced by aromatic groups increases the stability and loading capacity of polymeric micelles.

Fluorophore Labeling of Core-Crosslinked Polymeric Micelles for Multimodal In Vivo and Ex Vivo Optical Imaging

“…[16] The reagents were dissolved in DMSO at a monomer concentration of 300 mg/mL. The molar ratio of monomer-to-macroinitiator was 150/1, and that of HPMAm-Lac and ANHS was 4/1.…”

“…The polymer composition was evaluated by 1 H NMR as follow: (I) number of the HPMAm-Lac repeating units: in the 1 H NMR spectrum of the purified polymer, the integral at 3.4-3.6 ppm of methylene protons of mPEG 5000 was set as 448 (the average number of protons per one mPEG chain, M n =5000), and the integral value of the chemical shift at 4.1 ppm is assigned to the HPMAm-Lac repeating units. [16] (II) number of the ANHS repeating units: The mole fraction of vinyl protons of ANHS at 6.3 and 6.6 ppm relative to methylene protons of mPEG 5000 at 3.4-3.6 ppm in the crude product after polymerization was compared to that before the polymerization. GPC was conducted to determine the number average molecular weight (M n ), weight average molecular weight (M w ) and polydispersity (PDI, equal to M w /M n ) using two serial Plgel 5 μm MIXED-D columns (Polymer Laboratories) and PEGs of narrow molecular weight distribution as calibration standards.…”

“…[12][13][14] And furthermore, thermosensitive polymeric micelles, a special type of micelles formed using temperature-responsive amphiphilic block copolymers, are of great interest for targeted drug delivery purposes, because of their facile and robust micelle-formation process. [15][16][17][18] In recent years, significant efforts have been invested in visualizing and quantifying the biodistribution and the target site accumulation of nanomedicines using non-invasive imaging techniques. [19][20][21][22][23] Several different modalities, including positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), X-ray computed tomography (CT), ultrasound (US) and optical imaging (OI), have been employed for such purposes.…”

Co‐Delivery of Drugs and Genes Using Polymeric Nanoparticles for Synergistic Cancer Therapeutic Effects

“…While, a unique physical interaction, π-π stacking, was observed between aromatic group-containing drugs and aromatic group-containing coreforming polymers, which can increase the stability and loading capacity of micelles. [29] Depending on the interactions between the polymeric micelles and the drugs to be loaded, many techniques, such as solvent evaporation, salting-out and nanoprecipitation, have been developed. This topic has been reviewed comprehensively by Rao and Geckeler.…”

PEG-pHPMAm-based polymeric micelles loaded with doxorubicin-prodrugs in combination antitumor therapy with oncolytic vaccinia viruses

“…Many different drug delivery systems have been proposed to enhance the biodistribution and the tumor accumulation of chemotherapeutic drugs, and to thereby improve the balance between their efficacy and their toxicity [1][2][3][4][5][6][7][8] . In recent years, polymeric micelles based on poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl)-methacrylamidelactate] (mPEG-b-pHPMAmLac n ) have been investigated as biodegradable carriers of hydrophobic drugs, and have shown significant potential [9][10][11][12][13][14] . Doxorubicin (DOX) is a potent anticancer drug and commonly used as a model chemotherapeutic.…”