Our research in this area uses hybrid recombinant peptide polymers, the composition of which are inspired by Elastin-like Polypeptides (ELPs), Resilin-like polypeptide (RLPs), and their fusion with lipids, and bioactive peptides. By tuning the sequence and composition at the gene level we can tune their self-assembly with near absolute precision. Our goal is to find the “magic bullet” for anti-cancer therapy. We envision achieving this in four stages. In stage one we strive to increase passive targeting to the tumor: (i) by precise engineering of self-assembled particles in terms of shape, size, aspect ratio, mobility, dispersity and surface-charge density by exploiting phase transition behavior of the parent peptide/hybrid peptide backbones, and (ii) by incorporating stealth behavior to the nanoparticle by using a long-circulating peptide domain (like albumin-binding domain) or by redesigning the parent peptide. We showed that self-assembly of a zwitterionic peptide polymer that mimics synthetic PEG to significantly increase the plasma half-life of the nanoparticle, potentially avoiding antigenicity. In stage two we pursue homing the nanoparticle to tumor cells by decorating the nanoparticle with a tumor selective peptide-ligand at gene level. This avoids the drawbacks of covalent conjugation of ligand moiety, such as limited control of ligand valency, use of excess of ligand, manufacturing hassle etc. The targeting ability not only depends on ligand affinity but also on valency, shape of the particles and the linker with which it is attached to the particle surface. In stage three we aim to precisely optimize the drug binding domain (using lipids, canonical and non-canonical amino acids, cleavable linker etc) to mask small molecules in the nanoparticle core avoiding their premature leakage. Our motivation to demonstrate the versatility of our technology is reflected in our choice of drug that ranges from hydrophobic paclitaxel to hydrophilic gemcitabine, from bioactive peptide to inorganic metal ion like Pt. An ongoing effort is now directed towards combining this technology with our smart, tunable immunotherapy making it stage four in combating an established tumor.
Banskota, S.; Yousefpour, P.; Kirmani, N.; Li, X.; Chilkoti, A. Long Circulating Genetically Encoded Intrinsically Disordered Zwitterionic Polypeptides for Drug Delivery. Biomaterials 2019, 192, 475–485.
Yousefpour, P.; Ahn, L.; Tewksbury, J.; Saha, S.; Costa, S. A.; Bellucci, J. J.; Li, X.; Chilkoti, A. Conjugate of Doxorubicin to Albumin‐Binding Peptide Outperforms Aldoxorubicin. Small 2019, 15 (12), 1804452.
Yousefpour, P.; McDaniel, J. R.; Prasad, V.; Ahn, L.; Li, X.; Subrahmanyan, R.; Weitzhandler, I.; Suter, S.; Chilkoti, A. Genetically Encoding Albumin Binding into Chemotherapeutic-Loaded Polypeptide Nanoparticles Enhances Their Antitumor Efficacy. Nano Lett. 2018, 18 (12), 7784–7793.
Dzuricky, M.; Xiong, S.; Weber, P.; Chilkoti, A. Avidity and Cell Uptake of Integrin-Targeting Polypeptide Micelles Is Strongly Shape-Dependent. Nano Lett. 2019, 19 (9), 6124–6132.
Mozhdehi, D.; Luginbuhl, K. M.; Simon, J. R.; Dzuricky, M.; Berger, R.; Varol, H. S.; Huang, F. C.; Buehne, K. L.; Mayne, N. R.; Weitzhandler, I.; et al. Genetically Encoded Lipid-Polypeptide Hybrid Biomaterials That Exhibit Temperature-Triggered Hierarchical Self-Assembly. Nat. Chem. 2018, 10 (5), 496–505.
Mozhdehi, D.; Luginbuhl, K. M.; Dzuricky, M.; Costa, S. A.; Xiong, S.; Huang, F. C.; Lewis, M. M.; Zelenetz, S. R.; Colby, C. D.; Chilkoti, A. Genetically Encoded Cholesterol-Modified Polypeptides. J. Am. Chem. Soc. 2019, 141 (2), 945–951.
Luginbuhl, K. M.; Mozhdehi, D.; Dzuricky, M.; Yousefpour, P.; Huang, F. C.; Mayne, N. R.; Buehne, K. L.; Chilkoti, A. Recombinant Synthesis of Hybrid Lipid-Peptide Polymer Fusions That Self-Assemble and Encapsulate Hydrophobic Drugs. Angew. Chemie Int. Ed. 2017, 56 (45), 13979–13984.
Wang, J.; Dzuricky, M.; Chilkoti, A. The Weak Link: Optimization of the Ligand–Nanoparticle Interface To Enhance Cancer Cell Targeting by Polymer Micelles. Nano Lett. 2017, 17 (10), 5995–6005.
Wang, J.; Saha, S.; Schaal, J. L.; Yousefpour, P.; Li, X.; Chilkoti, A. Heuristics for the Optimal Presentation of Bioactive Peptides on Polypeptide Micelles. Nano Lett. 2019, 19 (11), 7977–7987.
Wang, J.; Min, J.; Eghtesadi, S. A.; Kane, R. S.; Chilkoti, A. Quantitative Study of the Interaction of Multivalent Ligand-Modified Nanoparticles with Breast Cancer Cells with Tunable Receptor Density. ACS Nano 2020, 14 (1), 372–383.
Costa, S. A.; Mozhdehi, D.; Dzuricky, M. J.; Isaacs, F. J.; Brustad, E. M.; Chilkoti, A. Active Targeting of Cancer Cells by Nanobody Decorated Polypeptide Micelle with Bio-Orthogonally Conjugated Drug. Nano Lett. 2019, 19 (1), 247–254.
Manzari, M. T.; Anderson, G. R.; Lin, K. H.; Soderquist, R. S.; Çakir, M.; Zhang, M.; Moore, C. E.; Skelton, R. N.; Fèvre, M.; Li, X.; et al. Genomically Informed Small-Molecule Drugs Overcome Resistance to a Sustained-Release Formulation of an Engineered Death Receptor Agonist in Patient-Derived Tumor Models. Sci. Adv. 2019, 5 (9).
Costa, S. A.; Simon, J. R.; Amiram, M.; Tang, L.; Zauscher, S.; Brustad, E. M.; Isaacs, F. J.; Chilkoti, A. Photo-Crosslinkable Unnatural Amino Acids Enable Facile Synthesis of Thermoresponsive Nano- to Microgels of Intrinsically Disordered Polypeptides. Adv. Mater. 2018, 30 (5), 1–9.
Bhattacharyya, J.; Bellucci, J. J.; Weitzhandler, I.; McDaniel, J. R.; Spasojevic, I.; Li, X.; Lin, C. C.; Chi, J. T. A.; Chilkoti, A. A Paclitaxel-Loaded Recombinant Polypeptide Nanoparticle Outperforms Abraxane in Multiple Murine Cancer Models. Nat. Commun. 2015, 6, 7939.
Bhattacharyya, J.; Weitzhandler, I.; Ho, S. B.; McDaniel, J. R.; Li, X.; Tang, L.; Liu, J.; Dewhirst, M.; Chilkoti, A. Encapsulating a Hydrophilic Chemotherapeutic into Rod-Like Nanoparticles of a Genetically Encoded Asymmetric Triblock Polypeptide Improves Its Efficacy. Adv. Funct. Mater. 2017, 27 (12).