Nanoparticle-laden Macrophage as a Tumor Tropic Drug Delivery System for Improved Cancer Treatment

Due to poor delivery efficiency, conventional chemotherapy usually requires high injection dose to achieve significant localized control of cancer, which unavoidably leads to systemic toxicity to normal tissues. The emerging nanotechnologies offer new opportunities in optimizing the therapy by altering the post-administration biodistribution of therapeutics and the interaction with the system¹. However, the improvement on delivery efficiency rendered by NP-based delivery system is somehow modest². Nowadays, naturally occurring living cells have been exploited as a new drug delivery system³. Compared with conventional chemotherapy and NP-based delivery strategy, cell-mediated drug delivery offers distinct advantages that are associated with the unique features of carrier cells. Typically, some cells, such as immune cells and stem cells, can be heavily recruited to injured or inflamed tissue, like tumor tissue, in response to various inflammation signals. Such a transmigration behavior makes such cells an ideal platform for delivery of imaging or therapeutic agents to tumor mass with high delivery efficiency.

In this project, we develop a NP-laden macrophage system to efficiently deliver doxorubicin (Dox), an anti-cancer drug, for improved cancer treatment. We first synthesize a Dox-encapsulated silica nanocapsule (DSN), then hitchhike DSNs into macrophages via internalization. To prevent early release of Dox during the tumor-tropic transmigration, which typically takes 6-24 hours, we coat an additional layer of silica onto DSN to reduce the drug release rate. Via a 2-hour co-incubation process, DSNs can be efficiently loaded into macrophages, achieving a loading capacity of 16.62 μg Dox per million cells. The treated macrophages retain high viability in the first 12 hours. Meantime, they are polarized to an M1 (classically activated) phenotype and retain comparable migration ability towards cancer cells as untreated macrophages do. Upon intravenous injection to mice bearing tumors, both untreated and DSN-laden macrophages accumulate in lung in the first hour and gradually accumulate to tumor mass in the next 8-24 hours. With gradual degradation of DSNs, Dox is liberated inside macrophages and shed to the surroundings, leading to apoptosis of tumor cells. Compared with free Dox treatment, DSN-laden macrophage offers improved tumor suppression and prolonged medium survival time but induces little systemic toxicity.

1. Chen, H. et al. Rethinking cancer nanotheranostics. Nat. Rev. Mater. 2, 17024 (2017).

2.  Wilhelm, S. et al. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014 (2016).

3.  Wang, Q. et al. Non-genetic engineering of cells for drug delivery and cell-based therapy. Adv. Drug Deliv. Rev. 91, 125–140 (2015).