Treatment with Pan-cancer Effective Drug Implemented Polymers in Brain Metastatic Mice Model

Introduction: Despite advance development of treatment strategies for brain metastasis (BM), challenges such as cancer-specific application limitations, drug resistance, and systemic side effects persist. In our perspective, effective BM treatment strategies should address at least two crucial aspects: 1) Achieving high central nervous system concentrations with direct tumor penetrance and 2) Selecting pan-cancer effective regimen against BM from heterogeneous origins. SN38, a highly potent metabolite of irinotecan hydrochloride, exhibits remarkable efficacy against various cancers. While direct use for BM treatment is effective, clinical application is limited due to SN38's water insolubility and high toxicity upon intravenous administration. The biodegradable PLGA polymer serve as good candidate for intra-tumoral SN38 drug delivery. The actioning time of SN38-embedded polymer could be adjusted according to the properties of drug molecules and the requirements of the drug release rate.

Methods: We established a BM mouse model using intracarotid artery injection in NOD-SCID mice. Under microscope guidance, luciferase-labeled lung cancer cell lines were injected into the carotid artery. The post-operative follow-up involved non-invasive imaging with XENOGEN IVIS system and a 7T animal MRI at various time points reveal 100% intracranial tumor formation and 0% extracranial disease. To address the efficacy of treatment with SN-38 eluting biopolymer in BM mouse model, we locally delivered SN-38 embedded PLGA polymer intra-tumorally, at the time when IVIS system confirmed the growth of intracranial BM tumor.

Results: Histological studies confirmed the adenocarcinoma characteristic and multifocal intracerebral lesions (7 tumor nodules / mice). Notably, 100% of leptomeningeal spreading was noticed along with tumor growth upon animal moribundity, compatible with BM patients nature course. The local implantation of SN38-PLGA showed high regional concentration while lowering the blood concentration. Tumor IVIS signal decreased after intracranial SN38-PLGA biopolymer implantation, and therefore prolonged survival after treatment compare to control group. Similar tumor growth inhibition was observed in MRI evaluation upto 2 week.

Conclusion : This approach holds promise for effective treatment with intra-tumoral implantation of SN-38-eluting PLGA biopolymer in BM disease.