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Abstract Background: Colorectal cancer (CRC) is a global health concern, with significant morbidity and mortality. Oxaliplatin (OXL) is a common treatment for CRC but its effectiveness is hampered by side effects, including gastrointestinal and neurotoxic effects. APX3330 exerts anti-angiogenic and neuroprotective effects. It is proposed that the combined use of OXL and APX3330-loaded nanoparticles (NPs) would improve drug delivery to cancer cells with enhanced therapeutic efficacy while reducing side effects of OXL. Methods: We developed dual-loaded NPs containing OXL and APX3330 linked to a cancer targeting monoclonal antibody (NPs+mAb). We characterized the physicochemical properties of the NPs and evaluated their cytotoxicity and drug release using CRC cell lines. In vivo, we assessed their therapeutic efficiency and side effects using an orthotopic CRC mouse model. Results: NPs exhibited an average size of 229±26 nm with a zeta potential of -24. 1±2. 1 mV. The drug loading and encapsulation efficiency were 3. 3±0. 2% and 71. 9%, respectively. Morphological analysis via scanning electron microscopy confirmed NP structure. In vitro drug release studies showed a slower release profile from NPs compared to free OXL, with a cumulative release of 34% (w/w) after 48 hours. Notably, cytotoxicity evaluation on CT-26 cells revealed a significant reduction in the IC50 for NPs compared to free APX3330 and OXL. In vivo studies demonstrated a remarkable 31% reduction in tumor growth rate in animals treated with NPs+mAb compared to those receiving free forms of OXL and APX3330. Body weight for animals treated with NPs+mAb remained similar to the healthy group, indicating minimal systemic toxicity. Moreover, the length of the colon in healthy organs remained steady compared to animals treated with OXL, which experienced a reduction in colon length. Animals treated with the free form of OXL exhibited diarrhoea, while the stool water content for animals treated with NPs+mAb remained at a similar level as the healthy group, suggesting reduced gastrointestinal side effects. Conclusions: This study demonstrates the potential of NPs with improved retention and encapsulation efficiency for effective drug delivery. Our research validates our novel method for creating NPs with mAb conjugation, enhancing cytotoxicity against CRC cell lines. In conclusion, the designed NPs+mAb formulation improves OXL treatment efficacy, providing targeted delivery of anti-cancer drugs to the tumor site and reducing tumor size while minimizing side effects. Citation Format: Niloufar Rashidi, Majid Davidson, Vasso Apostolopoulos, Mark R. Kelley, Kulmira Nurgali. Targeted combination nano-drug delivery system to enhance anti-cancer efficacy and reduce side effects abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 478.
Rashidi et al. (Fri,) studied this question.