Tumor-targeted iron-oxide nanoparticle (IONP) composition for the delivery of anti-PD-L1 peptides for treatment of cancers.
- Targeted delivery can reduce level of dosing and side effects.
- Peptides work by different mechanism than currently approved therapeutics.
- Added IONP core allows concurrent imaging during treatment.
- Nanoparticle enables ability to tether multiple compounds to a single IONP core.
Cancer is the leading cause of death in the developed world and the second leading cause of death in the developing world. PD-L1 is expressed in tumor cells and tumor associated stromal cells to suppress function of cytotoxic T cells. Anti PD-L1 antibodies or peptide blockers are a highly active area of oncology research for pharmaceutical companies. Problems still exist in many tumor types for which current anti-PD1 or PD-L1 antibody mediated therapies are difficult to deliver sufficient therapeutic dose due to the presence of drug delivery physical barriers. Results of clinical trials also showed that PD1/PDL-1 blocking alone only has limited success in a low percentage of cancer patients. A combination therapy is required to achieve therapeutic effect. Targeted therapies using nanoparticle drug carriers have the potential to deliver therapeutic agents into tumors and their metastatic lesions.
Dr. Yang’s group has shown that targeted IONPs have an improved capability of reaching tumors due to increased permeability of the tumor’s vasculature. Researchers at Emory University have developed tumor-targeting IONP composition for the delivery of peptides and activation of tumor-specific immune responses. This technology includes an IONP conjugated to a PD-L1 blocking peptide created by Dr. Yang’s team. The inventors have developed two PD-1 peptides, each containing a polyhistidine tag for conjugation to NTA-Cu functionalized IONPs. A PD-L1 inhibiting peptide conjugated ultra-small IONP has a similar size to an antibody, but can have 10 to 20 peptides bind to multiple PD-L1 on cells. Targeted delivery of the nanoparticles into tumors promotes infiltration of immune cells, including cytotoxic T cells. Carrying immune modulators, these nanoparticles are able to activate tumor specific immune responses. These compositions may serve as an alternative to current therapies based on observed, intratumoral delivery for cancers including melanoma, pancreatic, breast, liver, colon, prostate, and lung cancers.
Preliminary data demonstrated in vivo delivery of PD-1-IONPs