Thermosensitive Hydrogel Based on Poly(2-Ethyl-2-Oxazoline)-Poly(D,L-Lactide)-Poly(2-Ethyl-2-Oxazoline) for Sustained Salmon Calcitonin Delivery.

This study developed a thermosensitive hydrogel based on poly(2-ethyl-2-oxazoline)-poly(D,L-lactide)-poly(2-ethyl-2-oxazoline) (PPP) for the delivery of salmon calcitonin to improve the hypocalcemic effect. The tube inversion and rheological tests revealed that the copolymer solution underwent temperature-dependent sol-gel-sol transitions. Observation by scanning electron microscopy (SEM) showed that the hydrogel exhibited a porous three-dimensional network. The swelling test demonstrated that there was a maximum swelling ratio at low temperature (25°C) as compared with the high temperature (37°C). In vitro release revealed that the PPP hydrogel were capable of sustained release of salmon calcitonin (sCT). The in vivo biodegradability study indicated the good degradability of PPP hydrogel. More importantly, the in vivo retention time of the hydrogel in situ was significantly prolonged after subcutaneous injection of the PPP hydrogel compared to the F127 hydrogel. In vivo pharmacodynamics analysis showed that the hypocalcemic effect of both PPP and F127 hydrogel was significantly greater than that of sCT solution, and the mean serum Ca reduction effect could be maintained for 24 h of PPP hydrogel, indicating that PPP hydrogel could achieve a significant enhanced hypocalcemic effect. In conclusion, the PPP hydrogel has been shown to be prospective as a controlled release carrier for injection delivery of protein drugs.

Construction of α-Cyclodextrin-Based Stimuli-Responsive Gene Delivery Nanovectors: In Vitro, Ex Vivo, and In Vivo Investigations.

Stimuli-responsive materials are promising paradigm applied to construct diagnostic and therapeutic intracellular controlled release vectors, while highlighting many challenges and opportunities. In this paper, six α-cyclodextrin-based supramolecular nanovectors were constructed and the efficacy of amine groups, stimuli-responsive profiles and endocytic mechanisms were investigated. The results indicated that the designed supermolecules can compact DNA to form stable complexes and display low cytotoxicity. Among them, PRPEI-2 with suitable PEI amine group exhibited enhanced transfecting performance, high dilution stability, nice serum compatibility, and good acid-responsive profiles to enable endosome escape, significantly higher than commercially available transfecting agent PEI25000, the most effective vector studied to date. The endocytic uptake mechanisms involved in the transfection was mainly through clathrin-mediated pathway, which is closely associated with and can be improved by endosome escape. Moreover, PRPEI-2/DNA polyplex can be effectively expressed in vivo even after 48 h via only single tail-vein injection, and the gene expression and main tissue distribution appeared in the testis, liver, brain and spleen. These excellent characteristics demonstrated that the supramolecular PRPEI-2 represents an excellent prospect as stimuli-responsive nanovectors for gene diagnosis and therapy.