Resorufin-based ligand-functionalized nanogels for discoidin domain receptor inhibition and controlled drug delivery in ovarian cancer

The rational design of multifunctional nanomaterials capable of integrating molecular targeting and controlled drug delivery represents a key challenge in advanced cancer treatment. In particular, high-grade serous ovarian carcinoma remains one of the most lethal gynecological malignancies, characterized by chemoresistance and metastasis progression driven by tumor-stromal interactions, mediated by discoidin domain receptor 2 (DDR2). In this work, we report the design of hyaluronic acid/linear polyethyleneimine nanogels (NGs) as a dualfunctional platform combining receptor inhibition with chemotherapeutic payload delivery. NGs were functionalized with novel resorufin-based molecules rationally designed from the structural features of WRG-28, an allosteric DDR2 inhibitor, enabling stable covalent conjugation while preserving inhibitory activity. In particular, two original resorufin-based derivatives were rationally synthesized and labelled as WRG-A and WRG-B. WRG-A was proposed as a coupling-capable analog of WRG-28 (which lacks suitable functional groups for conjugation to biomaterial scaffolds), while WRG-B consists of a resorufin core bearing an amino-aliphatic spacer suitable for surface grafting. Both compounds were successfully conjugated onto the NG surface, yielding well-defined nanosystems with preserved colloidal stability and controlled surface functionality. The engineered NGs were subsequently loaded with cisplatin as a model chemotherapeutic agent and evaluated in OVCAR3 cells, representative of high-grade serous ovarian carcinoma. The functionalized nanoscaffolds demonstrated effective modulation of DDR2-mediated cell interactions in vitro, along with sustained intracellular drug delivery compared to free cisplatin and non-functionalized NGs. Overall, this work establishes a dual-functional NG-based platform integrating receptor-targeted inhibition and controlled drug release, providing a feasible strategy for the design of multifunctional colloidal systems for ovarian cancer treatment.