Discovering novel tumor-targeting surface chemistries using a library-based approach

During my PhD, I explored the tumor-targeting capabilities of a small library of bio-inspired surface chemistries, identifying a subset of carboxylated biopolymers that avidly bind to ovarian cancer (Correa et al. ACS Nano 2020). I found that when delivered via a systemic intraperitoneal injection, these coatings can direct more than 90% of nanoparticles to ovarian tumor tissues in vivo. Interestingly, despite chemical similarities in our top three coatings, the individual formulations exhibited distinct subcellular trafficking patterns. Nanoparticles coated with hyaluronic acid were internalized rapidly by cells into their endo-lysosomal compartment, a useful feature for delivery of a variety of drugs. Meanwhile, polyaspartic acid and polyglutamic acid coated nanoparticles presented unusual sub-cellular trafficking, with both formulations binding strongly to cancer cell membranes. However, while the polyglutamic-coated nanoparticles remained bound to the cell membrane for prolonged periods of time, the polyaspartic-coated particles were ultimately internalized via caveolar-mediated uptake.

The ability to specifically target these individual compartments provided us with the blueprints necessary to engineer novel nanomedicines. For example, the polyaspartic systems became the foundation for the development of a theranostic nanoparticle (Boehnke, Correa, Hao, et al. Angewandte Chemie 2020), where it was beneficial to extend nanoparticle residence time on the cell membrane but to also eventually enter the cell to delivery gene therapies. Likewise, the membrane-targeting polyglutamic acid coatings were used in an innovative cancer immunotherapy approach, where immunostimulatory proteins were delivered and retained on the surface of cancer cells to “paint” them for recognition by the immune system (Barberio et al. ACS Nano 2021).

Read more about these innovations here:

  1. Correa S, Boehnke N, Barberio AE, Deiss-Yehiely E, Shi A, Oberlton B, Smith SG, Zervantonakis I, Dreaden EC, Hammond PT. Tuning Nanoparticle Interactions with Ovarian Cancer through Layer-by-Layer Modification of Surface Chemistry. ACS Nano. 2020;14(2):2224-37.

  2. Boehnke N, Correa S, Hao L, Wang W, Straehla JP, Bhatia SN, Hammond PT. Theranostic Layer-by-Layer Nanoparticles for Simultaneous Tumor Detection and Gene Silencing. Angewandte Chemie International Edition. 2020;59(7):2776-83.

  3. Barberio AE, Smith SG, Correa S, Nguyen C, Nhan B, Melo M, Tokatlian T, Suh H, Irvine DJ, Hammond PT. Cancer Cell Coating Nanoparticles for Optimal Tumor-Specific Cytokine Delivery. ACS Nano. 2020;14(9):11238-53.