Penn 2012 iGEM Wiki

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Light-Activated Cytotoxic Drug Delivery

Problems With Current Targeted Therapies

Current therapies generally rely on either spatial targeting (targeting within a physical area) or cellular targeting (targeting to a specific antigen or biomarker).

Spatial Targeting: Surgeons excise a tumor manually, without

regard for cellular heterogeneity within and around the tumor area.

Cellular Targeting: Monoclonal antibodies identify antigens on certain cells or viruses. Monoclonal antibodies are often coupled with therapeutic agents.

However, if the antigen is present in healthy tissue outside the diseased area, it will be targeted as well.

These targeting mechanisms are imperfect on their own because they also target healthy tissue. Furthermore, the majority of therapies employ no targeting mechanisms at all (e.g. pharmacologic therapies). Even when diseases are clearly localized in specific areas and specific cells (such as cancer), current therapies such as chemotherapy attack the entire body and result in significant adverse effects. Patients who undergo chemotherapy suffer significant damage to fast-dividing cells throughout the entire body, which can result in immune system depression, hair loss, pain, and organ damage.

A Novel Therapeutic Platform

What if you could combine spatial targeting and cellular targeting into the same therapeutic? This idea is unprecedented but would allow for precise targeting of specific cells within a specific area, leaving healthy tissue intact and keeping side effects to a minimum.

The 2012 Penn iGEM team has engineered a novel platform for targeted therapeutics which employs simultaneous spatial and cellular targeting. We have achieved spatial (and temporal) targeting with a blue light-switchable transgene expression system, and cellular targeting through display of an antibody-mimetic protein on the surface of E. coli for the first time.

As a proof of concept, we applied our system to the treatment of cancer, a disease in which spatial and cellular targeting are of utmost importance. We displayed a high-affinity antibody-mimetic protein which targets Human Epidermal Growth Factor Receptor 2 (HER2), a protein commonly overexpressed in cancer cells. We combined this cellular targeting with a light-activated cytotoxic protein delivery system to successfully target and kill breast cancer cells.

Human Practices

Upon conception of this project, we realized that although hundreds of academic research projects and iGEM projects have been conducted in the realm of Health and Medicine, almost no engineered bacterial therapeutics have been brought to the clinic. We analyzed the hurdles and road ahead for bacterial synthetic biology-enabled therapeutics, compiling a thorough report with specific actions which iGEM teams in Health/Medicine can take to make their therapies more clinically tractable. This project directly informed our wet lab work, causing us to port our therapeutic system into a non-pathogenic, probiotic bacterial strain which is already used in human therapies today.

We hope our targeted therapeutic platform will allow other scientists and iGEM teams to target any cells they choose. In the near term, we are planning to test our cancer cell targeting/killing bacterial system in a mouse model and make a real impact on cancer research and therapy.