Novel Nanocarrier for Systemic and Intracellular Delivery of Biological Therapeutics

Background:

The stability and PK profile are of general concern for in vivo applications of many peptide/protein therapeutics. Poor stability of protein drugs can trigger immunogenicity. Furthermore, peptide and protein therapeutics mostly target extracellular receptors/signaling pathways and are impermeable to plasma membranes for interacting with the intracellular targets. Conventional nanoparticles designed for protein encapsulation and controlled release are generally associated with protein denaturation due to the extra manipulation together with unwanted chemical residues remaining in the formulation. The suite of technologies described herein seeks to overcome these challenges through molecular innovation in nanocarrier development for in situ protein encapsulation and intracellular protein delivery.

Technology Overview:

This innovative technology portfolio from Upstate Medical University provides multiple chemical formulations of telodendrimer nanocarriers made from biocompatible polyethylene glycol, amino acids, and natural hydrophobic compounds. The resulting nanocarriers binds to protein therapeutics via well-defined multivalent charge and hydrophobic interactions. Telodendrimer refers to a linear-dendritic copolymer, containing a hydrophilic segment (i.e., PEG or zwitterionic moiety) and one dendritic domain with the peripheral groups covalently capped with well-defined chemical moieties. Telodendrimers can be customized and optimized via computational and combinatorial approaches based on the charge and surface pocket of the cargo protein. These telodendrimers have well-defined flexible, multivalent, and hybrid branched functional domains for effective in situ protein encapsulation in solution driven by affinity.

Several types of proteins and peptides can be encapsulated in telodendrimers including, but are not limited to, cytokines, diphtheria toxin, cytochrome c, insulin, GLP-1 peptide, liragrutide, antibodies, growth factors, i.e., , VEGF, etc. This highly customizable nanotechnology platform permits the synthesis of nanocarriers to coat a variety of proteins in situ by simple addition of two solutions together forming both protein-friendly and patient-friendly formulation for in vivo applications. This telodendrimer coating significantly improves the PK profile in blood circulation with the capability to deliver cargo proteins intracellularly.

Advantages:

 

• Well-defined structures facilitating easy quality control and better reproducibility for regulation compliance;
• In situ protein encapsulation that avoids protein denaturation and unwanted chemical residues;
• Improved in vitro and in vivo protein/peptide stability and PK profiles;
• Intracellular delivery capability;
• High loading capacity: 20%-100% of the nanocarriers by weight;
• Maintenance of bioactivity of protein/peptide therapeutics for both topical and systemic delivery.

 Applications:

 

• Delivery of Insulin, GLP-1, Liraglutide for diabetes treatment.
• Intracellular delivery of diphtheria toxin, cytochrome C or antibodies for cancer treatment.
• Local delivery and control release of growth factors, e.g. VEGF, FGF for tissue regeneration.
• Improved systemic delivery of antibody therapeutics or enzymes or peptide/protein hormones with enhanced in vitro and in vivo stability, reduced immunogenicity and prolonged pharmacokinetic profiles.
• Delivery of cytokines for immune modulation therapy.

Intellectual Property Summary:

• Compositions and devices for removal of endotoxins and cytokines from fluids
• Functional, Segregated, Charged Telodendrimers and Nanocarriers and Methods of Making and Using the Same - EP3347053A1 and US20190292328A1
• Telodendrimers with Riboflavin Moieties and Nanocarriers and Methods of Making and Using the Same -WO2018136778A1 and US20190328742A1
• Zwitterionic dendritic amphiphiles, zwitterionic dendrimers, zwitterionic telodendrimers, nanocarriers comprising same, and methods of making and using same - WO2018160759A1 and US20200009069A1

Stage of Development:

• In vivo and ex vivo studies in mouse models for cancer, diabetes, psoriasis, and sepsis have been completed
• https://en.wikipedia.org/wiki/Technology_readiness_level

Licensing Status: 

Patented 

Licensing Potential: 

Seeking an industry partner to license the technology or partner to further technical development. 

Additional Information:

1. Shi C, Wang X, Wang L, Meng Q, Guo D, Chen L, Dai M, Wang G, Cooney R, Luo J.* A nanotrap improves survival in severe sepsis by attenuating hyperinflammation. Nat Commun. 2020 Jul 7;11(1):3384. https://www.nature.com/articles/s41467-020-17153-0
2. Guo, D., Shi, C., Wang, L., Ji, X., Zhang, S. & Luo, J.* Rationally Designed Micellar Nanocarriers for the Delivery of Hydrophilic Methotrexate in Psoriasis Treatment. ACS Applied Bio Materials 2020, 3, 8, 4832–4846 https://pubs.acs.org/doi/10.1021/acsabm.0c00342
3. Wang L, Shi C, Wang X, Guo D, Duncan TM, Luo J.* Zwitterionic Janus Dendrimer with distinct functional disparity for enhanced protein delivery. Biomaterials. 2019 Sep;215:119233. https://www.sciencedirect.com/science/article/pii/S0142961219303321
4. Wang X, Shi C, Zhang L, Bodman A, Guo D, Wang L, Hall WA, Wilkens S, Luo J.* Affinity-controlled protein encapsulation into sub- 30 nm telodendrimer nanocarriers by multivalent and synergistic interactions. Biomaterials. 2016 Sep;101:258-71. https://www.sciencedirect.com/science/article/pii/S0142961216302605
5. Wang X, Bodman A, Shi C, Guo D, Wang L, Luo J.*, Hall WA. Tunable Lipidoid-Telodendrimer Hybrid Nanoparticles for Intracellular Protein Delivery in Brain Tumor Treatment. Small. 2016 Aug;12(31):4185-92. https://onlinelibrary.wiley.com/doi/abs/10.1002/smll.201601234