All living creatures respond to external stimuli. Similarly, some polymers undergo conformational changes in response to changes in temperature, pH, magnetic field, electrical field, or the wavelength of light. In one type of stimuli-responsive polymer, thermogel polymers, the polymer aqueous solution undergoes sol-to-gel transition as the temperature increases. Drugs or cells can be mixed into the polymer aqueous solution when it is in its lower viscosity solution state. After injection of the solution into a target site, heating prompts the formation of a hydrogel depot in situ, which can then act as a drug releasing system or a cell growing matrix. In this Account, we describe key materials developed in our laboratory for the construction of biodegradable thermogels. We particularly emphasize recently developed polypeptide-based materials where the secondary structure and nanoassembly play an important role in the determining the material properties. This Account will provide insights for controlling parameters, such as the sol-gel transition temperature, gel modulus, critical gel concentration, and degradability of the polymer, when designing a new thermogel system for a specific biomedical application. By varying the stereochemistry of amino acids in polypeptides, the molecular weight of hydrophobic/hydrophilic blocks, the composition of the polypeptides, the hydrophobic end-capping of the polypeptides, and the microsequences of a block copolymer, we have controlled the thermosensitivity and nanoassembly patterns of the polymers. We have investigated a series of thermogel biodegradable polymers. Polymers such as poly(lactic acid-co-glycolic acid), polycaprolactone, poly(trimethylene carbonate), polycyanoacrylate, sebacic ester, polypeptide were used as hydrophobic blocks, and poly(ethylene glycol) and poly(vinyl pyrrolidone) were used as hydrophilic blocks. To prepare a polymer sensitive to pH and temperature, carboxylic acid or amine groups were introduced along the polymer backbone. The sol-gel transition mechanism involves changes in the secondary structures of the hydrophobic polypeptide and in the conformation of the hydrophilic block. The polypeptide copolymers were stable in the phosphate buffered saline, but the presence of proteolytic enzymes such as elastase, cathepsin B, cathepsin C, and matrix metallopreoteinase accelerated their degradation. We also describe several biomedical applications of biogradable thermogel polymers. One subcutaneous injection of the insulin formulation of thermogel polypeptide copolymers in diabetic rats provided hypoglycemic efficacy for more than 16 days. The thermogels also provided a compatible microenvironment for chondrocytes, and these cells produced biomarkers for articular cartilage such as sulfated glucoaminoglycan (sGAG) and type II collagen. The thermogels were also used as a fixing agent for in situ cell imaging, and cellular activities such as endocytosis were observed by live cell microscopy.
In the search for an enzymatically degradable thermogelling system, we are reporting poly(alanine-co-leucine)-poloxamer-poly(alanine-co-leucine) (PAL-PLX-PAL) aqueous solution. As the temperature increased, the polymer aqueous solution underwent sol-to-gel transition at 20-40 °C in a polymer concentration range of 3.0-10.0 wt %. The amphiphilic polymers of PAL-PLX-PAL form micelles in water, where the hydrophobic PALs form a core and the hydrophilic PLXs form a shell of the micelle. FTIR, circular dichroism, and (13)C NMR spectra suggest that the α-helical secondary structure of PAL is preserved; however, the molecular motion of the PLX significantly decreases in the sol-to-gel transition range of 20-50 °C. The polymer was degraded by proteolytic enzymes such as matrix metalloproteinase and elastase, whereas it was quite stable against cathepsin B, cathepsin C, and chymotrypsin or in phosphate-buffered saline (control). The in situ formed gel in the subcutaneous layer of rats showed a duration of ∼ 47 days, and H&E staining study suggests the histocompatibility of the gel in vivo with a marginal inflammation response of capsule formation. A model drug of bovine serum albumin was released over 1 month by the preset-gel injection method. The thermogelling PAL-PLX-PAL can be a promising biocompatible material for minimally invasive injectable drug delivery.
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