Collaborative Research: Integrative Adaptation of Dendrimer-peptide Conjugates for Cancer Immunotherapy

Non-technical Summary

Immunotherapy, utilization of a patient’s own immune system to treat diseases, has revolutionized cancer treatment. Most of the immunotherapeutic drugs that are being used in the clinic are based on biologics, such as antibodies (proteins that bind to specific antigens only), that boost immune surveillance against tumor cells. However, such antibody-based drugs are expensive and often result in disappointing clinical outcomes, particularly when used alone.

The use of peptides (macromolecules made from a chain of 20-30 amino acids) would be a promising alternative; however, their weaker binding than the corresponding antibodies has been recognized as a major weakness. Recently, the collaborative team proposing this work have demonstrated that small ball-shaped polymers (size of 1/10,000 of human hair thickness), called poly(amidoamine) (PAMAM) dendrimers, can be engineered to dramatically improve the binding strength of the peptides up to a million times.

In this proposal, the team hypothesizes that dendrimers attached with computationally optimized peptides can boost up the immune system to attack tumor cells, thereby maximizing their immunotherapeutic effect. Upon successful completion of this project, the team will contribute to developing a new technology that would be compatible with various immunotherapeutic peptides.

Integrated with the research effort, this project includes various educational activities that recruit graduate students, undergraduate students, and high school students. These activities will not only help advanced degree students be actively involved in cutting-edge science but also stimulate STEM interests of pre-college students, which will have profound impact on our nation to maintain the position as the world leader of science and engineering.

Technical Summary

The overarching goal of the research activities is to integrate computational and experimental methods to engineer a nanoparticle platform based on dendrimer-peptide conjugates for enhanced cancer immunotherapy. The collaborative team has demonstrated that poly(amidoamine) (PAMAM) dendrimers are excellent mediators for multivalent binding effects, as observed by dramatically enhanced binding avidities of small molecules, antibodies, and peptides.

This nanoengineering approach for binding enhancement could be directly applicable for improving cancer immunotherapy that relies on efficient blocking of binding between immune and tumor cells. Given that strong binding to the target immune checkpoint proteins, such as programmed death-ligand 1 (PD-L1), programmed cell death protein-1 (PD-1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), is necessary to effectively induce the checkpoint blockade, all the FDA-approved immune checkpoint inhibitors (ICIs) to date are based on antibodies with strong binding affinities.

Unfortunately, such antibody-based therapeutics are expensive and often result in disappointing clinical outcomes, particularly when used alone. The team hypothesizes that dendrimer conjugation with computationally optimized peptides that target multiple immune checkpoint receptors on T cells would substantially improve the binding strength of otherwise weakly binding peptides, which in turn would maximize their immunotherapeutic efficiency.

The use of peptides would be advantageous, as they are cost-effective and amenable to various engineering strategies, in contrast to whole antibodies. The proposed dendrimer-peptide conjugate (DPC) systems, consisting of engineered PAMAM dendrimers functionalized with peptides, are relatively simple in comparison to other commonly used nanoparticle drug delivery systems.

Yet, the DPC systems are unique and innovative in that: i) peptides can be adapted and optimized via a high-throughput computation; ii) dendrimers multimerize peptides to exploit strong multivalent binding effects (avidity); iii) folded peptides can be stabilized on the dendrimer surface, further contributing for binding enhancement; and iv) this approach is compatible with virtually any peptides, providing a modular platform for various combinations. Upon successful completion of this project, we will have obtained fundamental understanding in peptide design/synthesis, polymer engineering, and binding kinetics and biological behaviors of the DPCs.

The project will broaden participation of underrepresented minorities and women in STEM research at various educational levels.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.