3D printed, biodegradable, and biocompatible intraperitoneal implants loaded with folic acid-targeted/pH-sensitive/doxorubicin-loaded hydroxyapatite nanoparticles for systemic treatment of metastatic breast cancer

Three-dimensional porous scaffolds with the capability of controlled drug release have gained increasing interest in chemotherapy due to their sustained release of drugs and ability to reduce systemic toxicity. In this study, we advanced this concept by incorporating drug-loaded nanocarriers into 3D-printed scaffolds, creating trackable constructs for medical imaging such as CT-scan. Doxorubicin-loaded/folic acid-targeted pH-sensitive nanohydroxyapatite (Dox@nHA-FA) were synthesized and incorporated into gelatin/polycaprolactone/hydroxyapatite (Gel/PCL/HA) scaffolds via 3D printing. The Gel/PCL/HA(Dox@HA-FA) scaffolds were extensively characterized for drug release, mechanical strength, microstructure, and degradation profile. In vivo, scaffolds with different compositions were implanted in tumor-bearing Balb/c mice, and their degradation was monitored by CT-scan. The optimized scaffold composition shown medium disintegration tendency within 14 days and superior handling properties. In the orthotopic breast cancer model, Gel/PCL/HA(Dox@HA-FA) scaffolds produced a 71.8% reduction in tumor volume compared with untreated controls (P < 0.01), a 63.0% reduction versus free Dox (P < 0.05), and a 41.5% reduction versus Dox@HA-FA nanoparticles (P < 0.05). In addition, the number of metastatic liver colonies was reduced by ~65% compared with free Dox and by ~48% compared with Dox@HA-FA (P < 0.05). In the diffuse peritoneal metastasis model, Gel/PCL/HA(Dox@HA-FA) scaffolds led to a significant reduction (> 70%, P < 0.01) in peritoneal metastatic nodules, whereas the other groups showed widespread dissemination. Biocompatibility was confirmed by histopathology and blood biochemistry, with no significant alterations in liver or kidney function markers compared with healthy controls (P > 0.05). Importantly, the scaffolds' radio-opaque properties enabled non-invasive CT monitoring of degradation. Together, these results demonstrate that Gel/PCL/HA(Dox@HA-FA) scaffolds provide dual-targeted, sustained drug delivery with significant anti-tumor and anti-metastatic efficacy in vivo, supporting their potential for translation into local chemotherapy of advanced cancers.