We report a poly(ethylene glycol)-poly(L-alanine-co-L-phenylalanine) (PEG-PAF) aqueous solution as a polypeptide-based thermogelling system and its application as an injectable sustained release system for human growth hormone (hGH). The PEG-PAF aqueous solution underwent sol-to-gel transition at 16-34 C in a polymer concentration range of 6.0-14.0 wt% as the temperature increased. Dynamic light scattering, circular dichroism, FTIR, and 13 C-NMR spectra indicated that the secondary structure of PAF was preserved, however, PEG was dehydrated in the sol-to-gel transition temperature range. A micelle aggregation model was suggested for the sol-to-gel transition of the current PEG-PAF, similar to previous polyesters. The polymer was quite stable in water, and therefore, the molecular weight of the polymer did not significantly change and pH of the aqueous polymer solution was maintained at 7.2-7.8 during the 1 month storage of the polymer as an aqueous solution at room temperature. This point is clearly distinguished from previous thermogelling polymers based on polyesters, polyorthoesters, polyphosphazenes, poly(b-aminoester urethane)s, and polyanhydrides, which generate acid degradation products or can be degraded during storage as an aqueous polymer solution. Therefore, the current system can be used as a ready-to-use injectable implant for biomedical applications. When the polymer aqueous solution (0.5 mL) was injected into the subcutaneous layer of rats, the gel was formed by temperature-sensitive sol-to-gel transition, and the gel was completely eliminated from the implanted site in <15 days. A haematoxylin and eosin (H&E) staining study suggests the good histocompatibility of the gel in the subcutaneous layer of rats. As a sustained release formulation for hGH, the PEG-PAF showed a 4 day release profile with a pharmacological effective concentration range of >1-5 ng mL À1 in vivo, suggesting that the system is promising as a once-perweek delivery system for the hGH.
Bone-marrow-derived mesenchymal stem cells (BMSCs) were cultured in three-dimensional (3D) scaffolds formed by temperature-sensitive sol-to-gel transition of BMSC-suspended poly(ethylene glycol)-poly(L-alanine) (PEG-PA) aqueous solutions. A commercialized thermogelling 3D scaffold of Matrigel™ was used for the comparative study. The cells maintained their spherical shapes in the PEG-PA thermogel, whereas fibrous cell morphologies were observed in the Matrigel™. Type II collagen and myogenic differentiation factor 1 were dominantly expressed in the PEG-PA thermogel. On the other hand, a significant extent of type III β-tubulin was expressed in the Matrigel™ in addition to type II collagen and myogenic differentiation factor 1. After confirming the dominant chondrogenic differentiation of the BMSCs in the PEG-PA thermogel in in vitro study, in vivo study was performed for injectable tissue engineering application of the BMSCs/PEG-PA system. The cell-growing implant was formed in situ by subcutaneous injection of the BMSC-suspended PEG-PA aqueous solution to mice. In vivo study also proved the excellent expressions of chondrogenic biomarkers including collagen type II and sulfated glycosaminoglycan in the mouse model. This paper suggests that the PEG-PA thermogel is a very promising as a 3D culture matrix as well as an injectable tissue-engineering system for preferential chondrogenic differentiation of the BMSCs.
Poly(ethylene glycol)-poly(l-alanine-co-l-phenyl alanine) diblock copolymers (PEG-PAF) of 2000-990 Da (P2K) and 5000-2530 Da (P5K) with the different molecular weights of PEGs, but having a similar molecular weight ratio of hydrophobic block to hydrophilic block were synthesized to compare their solution behavior and corresponding protein drug release profiles from their in situ formed thermogels. The PEG-PAF aqueous solutions underwent heat-induced sol-to-gel transition in a concentration range of 18.0-24.0 wt % and 8.0-12.0 wt % for P2K and P5K, respectively. P5K formed bigger micelles than P2K, of a broad distribution, whereas the PAF blocks of P5K developed richer in α-helix than those of P2K in the core of the micelles. As the temperature increased, the micelles underwent dehydration of the PEG, which led to the aggregation of micelles, while the secondary structure of PAF was slightly affected during the sol-to-gel transition. The P5K exhibited higher tendency to aggregate and formed a tighter gel than P2K. Upon injection into the subcutaneous layer of rats, both polymer aqueous solutions formed a biocompatible gel with typical mild inflammatory tissue responses. Recombinant human growth hormone (rhGH) maintained its stability without forming any aggregates in both sol (4 °C) and gel (37 °C) states of the PEG-PAFs. Even though P2K and P5K have a similar molecular weight ratio of hydrophobic block to hydrophilic block, the P5K system exhibited a reduced initial burst release, improved bioavailability, and prolonged therapeutic duration of the rhGH, compared to the P2K system. The current research suggests that a drug release profile is a complex function of self-assembling carriers and incorporated drugs, and thus, a promising protein delivery system could be designed by adjusting the molecular parameters of a thermogel.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.