Biodegradable nanofibrous drug-eluting seed for sustained intratumoral immunotherapy
Abstract
Intratumoral immunotherapy presents a promising approach for enhancing cancer treatment; however, its effectiveness is limited by heterogeneous intratumoral drug distribution and rapid drug leakage following direct injection. To address these limitations, we developed a biodegradable nanofibrous drug-eluting seed (b-NDES), a reservoir-based implant designed for sustained, localized diffusive delivery of immunotherapeutics. The b-NDES reduces systemic exposure and eliminates the necessity for surgical removal through gradual biodegradation. Implant bodies were fabricated by electrospinning polymeric formulations co mprising varying ratios of polycaprolactone (PCL), poly(lactic-co-glycolic acid) (PLGA), and barium sulfate to provide radiopacity. Surface modifications were implemented to adjust the porous structure, allowing for tailored drug elution rates. Comparative comprehensive evaluations of morphology, in vitro release profiles, and degradation kinetics were performed. The optimized 1:4 PCL:PLGA formulation reduced permeable porosity from 18.99 ± 1.26% to 2.74 ± 1.04%, effectively decreasing the rhodamine delivery rate from 162.58 ± 16.11 μg/h to 30.68 ± 11.60 μg/h in vitro. The 1:4 PCL:PLGA structure achieved controlled diffusive drug release profile that extended intratumoral drug persistance in a 4 T1 triple-negative breast cancer (TNBC) murine model, with negligible systemic off-target exposure. Further, long-term degradation studies showed an overall mass loss of 46.32 ± 12.01% at 6 months. When loaded with a combination of CD40 agonist antibody (α-CD40) and a STING agonist (STINGa) and paired with stereotactic radiotherapy, the b-NDES platform achieved complete tumor eradication in 60% of animals and significantly prolonged survival. Importantly, no systemic adverse effects were observed with the intratumoral administration of the immunotherapeutic combination via b-NDES. By providing a minimally invasive, sustained-release strategy that naturally degrades to eliminate the need for surgical removal, the b-NDES represents a versatile platform for delivering potent immunotherapeutic combinations against aggressive malignancies. A polymeric solution of polycaprolactone (PCL), poly(lactic- co -glycolic acid) (PLGA), and barium sulfate (BaSO₄) is electrospun onto a rotating collector to generate a hollow cylindrical nanofibrous device. Following fabrication, the device is exposed to acetone vapor to promote partial fiber fusion, reducing inter-fiber porosity. This delivery platform, termed biodegradable nanofluidic drug-eluting seed (b-NDES), features a central cavity that serves as a drug reservoir for loading immunotherapeutic agents, which subsequently diffuse outward through fine pores within the nanofibrous wall. The b-NDES, loaded with a CD40 agonist antibody (α-CD40) and a STING agonist (STINGa), is evaluated in combination with radiotherapy in a 4 T1 triple-negative breast cancer murine model, achieving complete tumor eradication.