Preparation of PGA–PAE-Micelles for Enhanced Antitumor Efficacy of Cisplatin

Abstract

Poly-γ-l-glutamic acid (PGA) is an outstanding drug carrier candidate owning to its excellent biodegradability and biocompatibility. The PGA carrier may shield toxic drugs from the body and enable the delivery of poorly soluble or unstable drugs and thereby minimize the side effects and improve drug efficacy. However, the limitation of PGA as a drug carrier is low drug loading efficiency (DLE), which is usually below 30%. In this study, we reported a chemical modification method using l-phenylalanine ethyl ester (PAE). PGA-PAE construct was amphiphilic, which could form micelles in aqueous solution. Cisplatin (CDDP), a commonly used chemotherapy drug whose side effect is well-known, was used as a model molecule to test the drug-loading efficiency of PGA-PAE. In this paper, two sizes of CDDP-loaded PGA-PAE micelles (M(Pt)-1 and M(Pt)-2) were prepared, the average diameter of M(Pt)-1 was 106 ± 6 nm and M(Pt)-2 was 210 ± 9 nm. The DLE of M(Pt)-1 and M(Pt)-2 was 52.8 ± 2.2 and 55.8 ± 1.2%, respectively. Both exhibited excellent biocompatibility, stability, and drug-retaining capability in physiological condition. The in vitro accumulative drug-releasing profile, IC for different tumor cell lines HeLa, A549, and HCCC9810, and in vivo pharmacokinetics were similar between these two micelles; however, M(Pt)-1 showed higher tumor tissue retention and longer efficient cancer cell internalization time (up to 20 d). Our results suggested PGA-PAE micelle carriers reduced the toxicity of CDDP and its size at around 100 nm was the better for CDDP high-efficacy.

DOTA Functionalized Cross-Linked Small-Molecule Micelles for Theranostics Combining Magnetic Resonance Imaging and Chemotherapy

“…DLS showed that the hydrodynamic diameter of Gd@DOTA-CSMs was around 28 nm (Figure a). Finally, cisplatin mixed with the aqueous solution of 1 equiv AgNO 3 to generate the monoaqua complex cis-[Pt­(NH 3 ) 2 Cl­(OH 2 )] + and the theranostic nanoagent Pt/Gd@DOTA-CSMs was constructed by making cis-[Pt­(NH 3 ) 2 Cl­(OH 2 )] + coordinate with carboxylate ions of Gd@DOTA-CSMs at the 1:1 coordination mode, − which resulted in moderate increase of hydrodynamic diameter (∼37 nm, Figure b). Transmission electron microscopy (TEM) characterization further confirmed that the diameter of Pt/Gd@DOTA-CSMs was around 30 nm (Figure c).…”

Nanoscale Drug Delivery Systems in Glioblastoma

“…The inward-facing hydrophobic segments of copolymers serve as core in spherical PMs. In order to associate with the interior drugs, hydrophobic segments that possess various functional groups are commonly constructed by polyesters such as PLA [ 137 ], PGA [ 138 ] and PCL [ 139 ]. In addition, the camouflage outer layers of PMs play a pivotal role in stability and targeting.…”

<p>Burgeoning Polymer Nano Blends for Improved Controlled Drug Release: A Review</p>

“…PGA nanoparticles have been widely used as polymer-carriers for CDDSs due to their superb biodegradability and biocompatibility properties, which are being utilized for the targeted delivery of poorly soluble or unstable bioactive compounds bringing about low side effects and high drug loading efficacy. [194][195][196] Nevertheless, PGA has some limitations in CDDSs, such as insolubility in common solvents, problems in fabrication, high melting temperature (220°C) and high crystallinity of approximately 50%. 197,198 Accordingly, a naturally occurring anionic polypeptide γ-PGA-linked by the peptide bond among the α-amino and the abundant γ-carboxyl groups 30 -produced mostly using Bacillus subtilis bacteria 199 , has gained popularity on account of its satisfactory water solubility, favorable fiber-formation, film-forming ability, plasticity, and most greatly, for its activity in controlled drug release.…”