Hybrid Arborescent Polypeptide-Based Unimolecular Micelles: Synthesis, Characterization, and Drug Encapsulation

Abstract

This paper reports novel hybrid arborescent polypeptides based on poly­(γ-benzyl l-glutamate)-co-poly­(γ-tert-butyl l-glutamate)-g-polysarcosine [P­(BG-co-Glu­(OtBu))-g-PSar]. The synthesis is launched by ring-opening polymerization (ROP) of N-carboxyanhydride of γ-benzyl l-glutamate (BG-NCA) and γ-tert-butyl l-glutamate (Glu­(OtBu)-NCA) to synthesize a random copolymer P­(BG-co-Glu­(OtBu)) serving as a precursor for the arborescent system, followed by deprotection of the tert-butyl (tBu) groups to afford free COOH moieties serving as coupling sites. Two copolymerization reactions were carried out to afford the side chains. One type of side chain was a random copolymer P­(BG-co-Glu­(OtBu)), while the other type was a triblock copolymer PGlu­(OtBu)-b-PBG-b-PGlu­(OtBu). The peptide coupling reactions were conducted between the COOH moieties on the precursor and the terminus amine on the chain end of the P­(BG-co-Glu­(OtBu)) random copolymer or the PGlu­(OtBu)-b-PBG-b-PGlu­(OtBu) triblock copolymer to obtain G0 polymers. Afterward, hydrolyzing the tBu moieties of the G0 substrates yielded randomly functionalized G0 and end-functionalized G0. Randomly functionalized G0 was used as a substrate for the next generation G1 (randomly functionalized and end-functionalized G1 after deprotection) or coated with polysarcosine (PSar) to gain G0-g-PSar. The G0 substrate prepared with the triblock copolymer PGlu­(OtBu)-b-PBG-b-PGlu­(OtBu) was only grafted with PSar after deprotection, resulting in G0-eg-PSar. Depending on the functionality mode of the G1 substrate, the PSar coating yielded two different graft polymers, G1-g-PSar and G1-eg-PSar, for randomly functionalized and end-functionalized G1, respectively. The PSar hydrophilic shell was decorated with the sequence of (arginine, glycine, and aspartic acid) tripeptides (RGD) as a targeting ligand to improve the potentiality of the arborescent unimolecular micelles as drug carriers. Preparative size exclusion chromatography (SEC) was used to fractionate these complex macromolecular architectures. Nuclear magnetic resonance (NMR), Fourier-transform infrared (FTIR), Raman spectroscopy, and SEC were used for molecular characterization of all intermediate and final products and dynamic light scattering (DLS), transmission electron microscopy (TEM), and atomic force microscopy (AFM) for micellar characterization. A comparison between randomly grafted (g) and end-grafted (eg) unimolecular micelles demonstrates that the former has an undefined core–shell structure, unlike its end-grafted analog. In addition, this study has proved that decoration of the shell with RGD contributed to avoiding micelle aggregation but limited chemotherapy agent encapsulation. However, more than their naked analog, the sustained release was noticeable in decorated micelles. Doxorubicin was utilized as a chemotherapy model, and loading was achieved successfully by physical entrapment.

Toward Synthetic Intrinsically Disordered Polypeptides (IDPs): Controlled Incorporation of Glycine in the Ring-Opening Polymerization of N-Carboxyanhydrides

“…BLG-NCA affords poly­(γ-benzyl- l -glutamate) (PBLG) which is a helical polymer with biomimetic secondary structuring properties, while its deprotected form, polyglutamic acid (PGA), is water-soluble and pH-responsive . Polymers ,,, and copolymers , of PBLG or PGA derivatives have potential applications in bioactive substance delivery, − and the preparation of antibacterial agents or biomaterials …”

Unimolecular micelles from star-shaped block polymers by photocontrolled BIT-RDRP for PTT/PDT synergistic therapy

“…In recent years, the application of UIMs in tumor therapy has received increasing attention due to their excellent stability in the microenvironment of living organisms and unexpected effects through the enhanced permeability and retention effect of solid tumors. 25,26 A variety of studies have been conducted to show their excellent performance in drug delivery, 27 in vivo imaging, 28 chemotherapy, 29 photothermal therapy, 30 photodynamic therapy 31 and so on. Compared with traditional chemotherapy and radiotherapy, photothermal therapy (PTT) and photodynamic therapy (PDT) are two minimally invasive, highly effective optical therapies with few side effects, which have become a hot research spot in the field of tumor treatment.…”

Micelle encapsulation zinc‐doped copper oxide nanocomposites reverse Olaparib resistance in ovarian cancer by disrupting homologous recombination repair

“…However, due to their special structure, Zn‐CuO NPs suffer from low solubility. Polymeric micelles as a novel drug delivery system have the advantages of prolonging drug circulation time, enhancing drug accumulation, improving drug dissolution range, and reducing side effects 33 . In this study, we used surfactants and polyether polyol as stabilizers to prepare stabilized nanoparticles by strong ultrasound technique encapsulation to enhance the durability of metal nanoparticles, reduce their accumulation, enhance their distribution, and form a nanosystem of 50‐nm metal nanomicelles.…”

“…Polymeric micelles as a novel drug delivery system have the advantages of prolonging drug circulation time, enhancing drug accumulation, improving drug dissolution range, and reducing side effects. 33 In this study, we used surfactants and polyether polyol as stabilizers to prepare stabilized nanoparticles by strong ultrasound technique encapsulation to enhance the durability of metal nanoparticles, reduce their accumulation, enhance their distribution, and form a nanosystem of 50‐nm metal nanomicelles. We continued the characterization using transmission electron microscopy (TEM) and found that the metal nanoparticles were dispersed in the interior of the micellar system and the micellar encapsulation improved the homogeneity of the metal nanoparticles.…”