DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

The Use of Polycationic Uptake Peptides for Fluorescence-Guided Surgery

Posted October 26, 2016
Roger Tsien, Ph.D., University of California San Diego School of Medicine

Kornelia Polyak, M.D., Ph.D (Front row, third person from the right) Dana-Farber Cancer Institute
Roger Tsien, Ph.D. (1952 - 2016)
Photo used with permission of
the University of California, San Diego

Dr. Roger Tsien, a 2008 Nobel Laureate, spent his entire career designing and building bioactive molecules before passing away in August 2016. He was known for improving and altering the colors of the Green Fluorescent Protein (GFP), which became the first means to genetically encode robust visible fluorescence. This sparked a revolution in molecular and cell biology, since many intracellular proteins and processes can now be visualized and better understood. Most of the enhanced fluorescent proteins now in use stem from his laboratory. In addition to work on modifications of GFP, Dr. Tsien developed small cell-penetrating peptides (6-12 amino acids long) to which membrane-permeant small dye molecules will bind extremely tightly in living cells. These polycationic peptides-peptides that have either an abundance of positively charged amino acids or an alternating pattern of charged amino acids-permit techniques beyond the capabilities of autofluorescent proteins, such as electron-microscopic localization and highly targeted imaging on the cellular and subcellular levels.

With support from the Breast Cancer Research Program (BCRP) FY04 Innovator Award, Dr. Tsien set out to lay the foundation for clinical trials of imaging and therapeutic agents based on the science of the cell-penetrating polycationic peptides and their ability to transport dyes and therapeutic cargo. His goal was to be able to detect and treat solid tumors, including those arising from breast cancer. With this award, Dr. Tsien was able to develop a new mechanism to concentrate imaging and therapeutic agents on and within cells in the immediate vicinity of cleavage proteins that are typically upregulated in solid and metastatic tumors. Not only would these peptides eventually be able to deliver therapeutics, but they could also be used for fluorescence-guided surgery, allowing surgeons to visualize the tumor with a high degree of sensitivity and specificity to permit more-complete tumor resection. With his BCRP award, Dr. Tsien built a second-generation intraoperative surgical system that can simultaneously image two different fluorophores (using two precisely co-registered monochrome cameras) along with a reflectance image (from a color camera). He also discovered the importance of counterstaining nerves to show the margins of operations and focused on determining the binding location and structure-activity relationship of the existing nerve-staining peptide.

Since the completion of Dr. Tsien's award in FY11, much has been accomplished with the peptides and mechanisms developed with the support of the BCRP. An in vivo fluorescent protease-activatable peptide, AVB-620, that detects, marks, and visualizes cancer has been licensed by Avelas Biosciences and is currently in the final stages of a Phase Ib clinical trial in breast cancer to test for safety and tolerability (ClinicalTrials.gov identifier NCT02391194). AVB-620 is given to patients intravenously prior to surgery, and the dose and timing needed to generate a fluorescence signal in tumor and lymph node tissue is being evaluated. If successful, the use of AVB-620 will help surgeons make medical decisions in real-time by identifying critical cancer margins for tumor resection and examining lymph nodes for invasive disease. More precise tumor resection aided by AVB-620 may enable patients to avoid reoperations as well as highly invasive axillary lymph node dissection, while obtaining more accurate disease staging.


Publications:

Aguilera TA, Olson ES, Timmers MM, et al. 2009. Systemic in vivo distribution of activatable cell penetrating peptides is superior to that of cell penetrating peptides. Integr Biol 1:371-381.

Olson ES, Aguilera TA, Jiang T, et al. 2009. In vivo characterization of activatable cell penetrating peptides for targeting protease activity in cancer. Integr Biol 1:382-393.

Nguyen QT, Olson ES, Aguilera TA, et al. 2010. Surgery with molecular fluorescence imaging using activatable cell-penetrating peptides decreases residual cancer and improves survival. Proc Natl Acad Sci USA 107:4317-4322.

Olson ES, Jiang T, Aguilera TA, et al. 2010. Activatable cell penetrating peptides linked to nanoparticles as dual probes for in vivo fluorescence and MR imaging of proteases. Proc Natl Acad Sci USA 107:4311-4316.

Ting R, Aguilera TA, Crisp JL, et al. 2010. Fast 18F labeling of a near-IR fluorophore enables PET/optical imaging of sentinel lymph nodes. Bioconj Chem 21(10):1811-1819.

Whitney M, Olson ES, Aguilera TA, et al. 2010. Parallel in vivo and in vitro selection using phase display identifies protease dependent tumor targeting peptides. J Biol Chem 285:22532-22541.

Stummer W, Ton JC, Mehdorn HM, et al. 2011. Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. Clinical Article. J Neurosurg 114(3):613-623.

Whitney MA, Crisp JL, Nguyen LT, et al. 2011. Fluorescent peptides can highlight peripheral nerves during surgery. Nat Biotechnol 29:352-356.

Olson ES, Whitney MA, Friedman B, et al. 2012. In vivo fluorescence imaging of artherosclerotic plaques with activatable cell-penetrating peptides targeting thrombin. Integr Biol 4(6):595-625.


Links:

Public and Technical Abstracts: Targeting Contrast and Therapeutic Agents to Tumors via Selective Unleashing of Polycationic Uptake Peptides

Public and Technical Abstracts: Hybrid Nanotechnologies for Detection and Synergistic Therapies for Breast Cancer

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Last updated Wednesday, October 26, 2016