Significant efforts have been devoted to the development of nanoparticular delivering systems targeting tumors. However, clinical applications of nanoparticles is hampered by insufficient size homogeneity, difficulties in reproducible synthesis and manufacturing, frequent high uptake in the liver, systemic toxicity of the carriers (particularly for inorganic nanoparticles) and insufficient selectivity for tumor cells. We have recently discovered the ability of properly modified transmembrane peptides to assemble into remarkably uniform spherical nanoparticles with innate biological activity. Self-assembly is driven by a structural transition of the peptide that adopts predominantly a beta-hairpin conformation in aqueous solutions, but folds into an alpha-helix upon spontaneous fusion with cell membrane. Alpha-helical peptide interferes with proper assembly of the target receptor and inhibits its function. The best characterized antagonist inhibits signaling through CXCR4 inhibitor with IC50=100 nM. Addition of polyethylene glycol (PEG) chains of up to 27 monomeric units stabilizes nanoparticles and prevents their super-aggregation without interfering with biological activity. Longer PEG chains diminish efficient fusion of nanoparticles with the cell membrane and reduce anti-receptor activity.The peptide self-assembles with such high efficiency that critical self-assembly concentration (CAC) could not be determined by traditional methods, such as dynamic light scattering, ultracentrifugation or viscosimetry. We have developed a new method of CAC determination based on Microscale Thermophoresis. The determined CAC is in nanomolar range for all peptides tested, in good agreement with observed high precision of self-assembly and stability of the nanoparticles. Nanoparticles efficiently encapsulate poorly soluble hydrophobic drugs, thus providing a unique delivery system with dual anti-tumor activity. Even empty nanoparticles effectively inhibit lung metastasis in a mouse model of human breast tumor, due to their ability to inhibit CXCR4 receptor signaling. We have now developed nanoparticles that fuse with cells in receptor-mediated manner, similar to viruses. Conjugates of self-assembling peptide to ligands of receptors overexpressed on prostate tumors resulted in nanoparticles that fuse more effectively with cells expressing corresponding receptor. Self-assembling virus-like particles with intrinsic biological activity present a new paradigm in anti-cancer drug development. We have now generated fully synthetic self-assembling nanoparticles that fuse with cells in receptor-mediated manner, like natural viruses. Synthetic particles were designed to fuse with cells through three receptors over expressed on prostate tumor cells: gastrin-releasing peptide receptor, luteinizing hormone releasing peptide receptor and prostate-specific membrane antigen. All three synthetic virus-like particles have been shown to fuse with cells very selectively: blocking the corresponding receptor with its ligand completely prevents cell fusion. Fluorescence tomography studies in mice have demonstrated that new fully synthetic virus-like particles localize to prostate tumors with high efficiency and selectivity. The particles are promising agents for both imaging and therapy of prostate tumors. We have also developed recently self-assembling antagonists of CCR3 receptor that plays a critical role in pathogenesis of asthma. The compounds are promising agents for the treatment of the disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011307-07
Application #
9343869
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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