Abstract:
Precise local delivery of chemotherapeutic agents
employing an injectable depot could be a promising approach to
achieve spatiotemporal control over the drug release along with
minimizing the challenges associated with the systemic delivery of
chemotherapeutic agents. In this regard, we report the development and
evaluation of a poly(ethylene glycol) (PEG) hydrogel-based drug
delivery platform for the covalent entrapment and sustained release of
chemotherapeutic agents. The hydrogels were fabricated by crosslinking of 8-arm PEG glyoxylic aldehyde and 8-arm PEG hydrazine
using glyoxylic hydrazone linkages, without employing small-molecule
cross-linkers. The hydrogels displayed pH-responsive gelation and
swelling pattern along with mechanical robustness, with storage
modulus of up to 1650 Pa. Owing to the reversible nature of glyoxylic
hydrazone linkages, hydrogels exhibited excellent thixotropic and self-healing characteristics. Doxorubicin (DOX) was
covalently entrapped into the hydrogel matrix by attaching it to 8-arm PEG hydrazine in substoichiometric ratios, prior to
fabrication of hydrogels. A controlled release of up to 81.33% DOX was obtained from 5% hydrogels after 40 days at tumoral
pH (6.4 ± 0.05) and only 42.87% DOX at physiological pH (7.4 ± 0.05). The 3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide assay and three-dimensional cell encapsulation studies using NIH-3T3 cell lines demonstrated the
biocompatible nature of polymers as well as the hydrogel matrix. The multicellular tumor spheroid growth suppression studies
demonstrated a 40.50% reduction in tumor area for the PEG−DOX conjugate, while a 29.27% reduction for hydrogel release
media and 51.9% for the DOX. Both PEG−DOX and the release media were internalized into A549 cells, causing cell death.
The present strategy can be employed for long-term sustained delivery of chemotherapeutic agents to locally accessible tumors.
