Synthesis and biocompatibility of dual-responsive thermosonic injectable organogels based on crosslinked N-(isopropyl acrylamide) for tumour microenvironment targeting.

A series of three dual-responsive 'thermosonic' (thermo- and ultrasound-responsive) injectable organogels (TIOs) based on crosslinked N-(isopropyl acrylamide) (NIPAM) bearing biocompatible polymeric constituents were investigated for strong gelation in response to tumour temperature, and sol-like fluid gel formation upon the application of an ultrasonic stimulus. A time-efficient free radical polymerisation reaction of ˂15 min resulted in TIO formation. Moreover, the formulation of the TIOs integrated green chemistry principles to ensure enhanced biocompatibility. Fourier Transform Infrared (FTIR) spectral analysis revealed the presence of new molecular vibrations at 847 and 771 cm-1 (CH deformation), which were indicative of the functionalisation of the NIPAM backbone with hydrophobic and ultrasound-responsive aromatic moieties. Thermo- and ultrasound-response analysis and rheological analysis demonstrated that the TIOs displayed a temperature-induced transition to a strong highly-structured gel, and an ultrasound-triggered increase in gel flowability dependant on the composition of the formulation. Cell proliferation studies were undertaken for the TIOs, which verified that the designed TIOs were all non-cytotoxic and promoted cell proliferation over 1, 3, and 5 day intervals. The rational design and formulation of a biocompatible injectable in-situ depot drug delivery system for ultimate application in tumour targeting was successfully achieved and warrant further investigation.