Control of rhGH Release Profile from PEG–PAF Thermogel

Abstract

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.

Fine tuning the assembly and gel behaviors of PEGylated polypeptide conjugates by the copolymerization of l‐alanine and γ‐benzyl‐l‐glutamate N‐carboxyanhydrides

“…As shown in Figure , PEA and PEAB‐1 hydrogels showed highly porous interpenetrating network structures with microscale pores. The three‐dimensional (3D) network with pores can be used as a depot for controlled drug release, cell culture, or micro/nanoparticle delivery . PEAB‐2 and PEAB‐3 aggregates showed fractured microstructures without obvious network morphologies because no hydrogel transition occurred for their solutions.…”

“…Depending on their assembly, the obtained architectures have a various range of physicochemical and mechanical properties associated with their applications. Generally speaking, self‐assembled peptide structures are of their own advantages in encapsulation of hydrophobic drugs, sustained drug release, biocompatibility, stability, culture environment for cells, and/or immunoadjuvant properties . To modulate the assembled architectures, polyethylene glycol (PEG) is usually linked to the polypeptide block to prepare PEGylated peptide copolymers, such as PEG‐poly(γ‐benzyl‐ l ‐glutamate), PEG‐polytyrosine, and PEG‐poly( l ‐alanine), by conjugation or using PEG as the initiator of the ring‐opening polymerization of α‐amino acid N ‐carboxyanhydrides (NCA) .…”

“…Generally speaking, self-assembled peptide structures are of their own advantages in encapsulation of hydrophobic drugs, sustained drug release, biocompatibility, stability, culture environment for cells, and/or immunoadjuvant properties. [23][24][25][26][27][28][29][30] To modulate the assembled architectures, polyethylene glycol (PEG) is usually linked to the polypeptide block to prepare PEGylated peptide copolymers, such as PEG-poly(c-benzyl-L-glutamate), PEG-polytyrosine, and PEGpoly(L-alanine), by conjugation or using PEG as the initiator of the ring-opening polymerization of a-amino acid N-carboxyanhydrides (NCA). 6,9,23,31,32 Commonly, during the peptide copolymer assembly process, PEG serves as the hydrophilic segment, while peptide segments form the hydrophobic microdomians through hydrophobic interaction, and a-helix or b-sheet mediated peptide chain stack.…”

Biodegradable Thermogelling Polymers

“…These thermosensitive copolymers have been grafted with a variety of biocompatible and biodegradable components containing hydrolysable backbones or easily oxidized side groups, such as poly(D,L‐lactic acid‐co‐glycolic acid) (PLGA), poly(L‐lactic acid) (PLLA), poly(ε‐carprolactone) (PCL) or polycaprolactone diol, poly([R]‐3‐hydroxybutyrate) (PHB), poly(organophosphazene), poly(propylene phosphate), polyacetal, and poly(ortho ester) . Polypeptides with unique biodegradability, thermosensitivity due to self‐assembled secondary or tertiary structures and ionic side groups for customizability, such as poly(L‐alanine) and poly(L‐alanine‐co‐L‐phenyl alanine), are also excellent alternatives. PEG–PLGA–PEG was the first reported biodegradable thermosensitive block copolymer.…”

Multi-responsive polypeptide hydrogels derived from N-carboxyanhydride terpolymerizations for delivery of nonsteroidal anti-inflammatory drugs

“…12, 13 The high water content and tunable properties of these materials render them suitable synthetic mimics of soft tissue microenvironments, as well as promising media for localized storage and delivery of therapeutic agents. 14, 15 In addition, the controlled incorporation of supramolecularly noncovalent interactions or chemically covalent linkages into hydrogelators yields hydrogels that respond to various physical, chemical or biological stimuli. 16, 17 Regulated reorganizations within the three-dimensional structures and transitions between the sol and gel states provide tunable release rates of encapsulated small molecules.…”