A Cell‐Delivered and Cell‐Activated SN38‐Dextran Prodrug Increases Survival in a Murine Disseminated Pancreatic Cancer Model

Abstract

Enzyme activated prodrugs have been investigated and sought after as highly specific, low side effect treatments, especially for cancer therapy. Unfortunately, excellent targets for enzyme activated therapy are rare. Here we demonstrate a system based on cell delivery that can carry both a prodrug and an activating enzyme to the cancer site. Raw264.7 cells (mouse monocyte/macrophage like cells, Mo/Ma) were engineered to express intracellular rabbit carboxylesterase (InCE), which is a potent activator of the prodrug irinotecan to SN38. InCE expression was regulated by the TetOn® system, which silences the gene unless a tetracycline, such as doxycycline, is present. Concurrently, an irinotecan-like prodrug, conjugated to dextran, was synthesized that could be loaded into the cytoplasm of Mo/Ma. To test the system, a murine pancreatic cancer model was generated by intraperitoneal (i.p.) injection of Pan02 cells. Engineered Mo/Ma were loaded with the prodrug and were injected i.p. Two days later, doxycycline was given i.p. to activate InCE, which activated the prodrug. A survival study demonstrated that this system significantly increased survival in a murine pancreatic cancer model. Thus, for the first time, a prodrug/activating enzyme system self-contained within tumor-homing cells has been demonstrated that can prolong the life of i.p. pancreatic tumor bearing mice.

Prodrug and nanomedicine approaches for the delivery of the camptothecin analogue SN38

“…SN38-dextran) was synthesised and was more efficiently loaded into Mo/Ma cells and the drug loading was 10 μg/ml [108]. Treatment using the SN38-dextran loaded Mo/Ma cells in conjunction with doxycycline showed 10% longer survival time in a murine disseminated pancreatic cancer model, in comparison to the SN38 control group.…”

“…Bioengineered and tumour-homing cells have been utilised as targeted delivery carriers of both SN38 prodrugs and the prodrugactivating enzyme [107][108][109]. For example, RAW 264.7 cells (mouse monocytes/macrophage-like cells, Mo/Ma) for inducible expression of carboxylesterase have been engineered.…”

Macrophage mediated biomimetic delivery system for the treatment of lung metastasis of breast cancer

“…For the proof of concept, RAW264.7 cells, a kind of mouse macrophage-like cell line with similar functions to primary macrophage cells, were used here as the cell carriers. RAW264.7 cells are often used as cellular vehicles by other investigators [5,[18][19][20] and also employed as the model of tumorassociated macrophages [20]. Then, for the first time, doxorubicin (DOX) loaded RAW264.7 cell delivery system was constructed and related studies in vitro and in vivo including its tumor homing ability, anti-cancer efficacy and toxicity to main organs in a mouse model of lung metastasis of breast cancer, were conducted.…”

“…However, the drug loading content seems too low to be clinically meaningful in most cases. To reduce the harmfulness of treating agents to the cellular vehicles themselves, some studies anchored drug containing nanomaterials at the surface of cells by chemical reactions [14][15][16][17], while others developed a BDS by linking prodrug to the related enzyme expressing macrophages [18,19]. These systems exhibited minimal toxicity to the cellular vehicles and healthy tissues, but perhaps the complicated operating procedures resist their possible clinical application.…”

Cells As Delivery Vehicles for Cancer Therapeutics

“…Combining the concept of delivering nanoparticles and delivering a chemotherapy drug, an irinotecan-like prodrug was synthesized on iron/iron oxide nanoparticles in order to increase loading and retention in the Raw264.7 cells. Using these cells to deliver the SN38 prodrug and treating with doxycycline significantly increased survival in a model disseminated pancreatic cancer [85].…”