#5 A carbohydrate-encapsulated gold nanoparticle used to inhibit metastasis of cancer cells
NIH Title: Carbohydrate-Encapsulated Gold Nanoparticles as Novel Anti-Metastatic Agents
NIH Reference Number: E-001-2005
Executive Summary:
General Description:
Tumor-associated carbohydrate antigens (TACA) are glycan chains expressed on the tumor cell surface, and rarely observed on the surface of the non-malignant cells. Fully processed, these carbohydrates on tumors lead to malignant cellular consequences such as modified cell adhesion, enhanced aggression, and metastasis.
Two widely distributed TACAs are Thomsen-Friedenreich (TF) disaccharide antigen and its corresponding “T nouvelle” (Tn) monosaccharide antigen. TF and Tn antigens are classic carbohydrate antigens that are shielded in healthy and benign-diseased tissues, but are uncovered in about 90% of carcinomas (e.g., breast, colon, prostate, bladder, ovarian, and gastric). The TF-bearing glycoproteins are believed to bind to carbohydrate-binding proteins on the surface of endothelial cells or shed from those site. This in turn repolarizes the tumor cell surface to expose other cell-adhesion molecules (e.g., integrins) to facilitate strong binding of the tumor cells to the endothelial surface leading to tumor cell colonization and metastasis. Scientists have been targeting these carbohydrate antigens to generate tumor-specific immunotherapy, or to inhibit the tumor-specific cell adhesion.
Cell surface glycan also plays important roles in the pathology of many other diseases such as inflammation, restenosis, bacterial/viral infections; therefore, the therapeutic could potentially be used for these indications.
Scientific Progress:
The researchers discovered an efficient way of preparing tumor antigen-containing glycopeptide building blocks from novel pentenyl glycosides. They further successfully synthesized TF-glycoamino acid conjugates attached to AuNP through a combined alkane/PEG linker, where the TF was attached to either a serine or threonine amino acid. TF-bound particles inhibited the growth of Galectin-3 positive tumor cells more significantly in vitro than that of the Galectin-3 negative tumor cells.
Recently, the researchers described the procedure of preparing a glyconanaoparticle that also contains peptides and linkers for cancer vaccination. The self-assembled particle was very stable and withstood repeated lysophilization and reconstitution. The molar ratio of the thiols used in the synthesis was 1:1:3 (MUC4 peptide/glycopeptide):(C3d peptide):(linker 6). In their study, the ligand coverage was estimated by calculating the particle surface area and the reactant concentration. They injected the vaccine particles into the mice (groups of 20), and tested the serum IgM and IgG level enzyme immunoassay afterwards. Vaccination significantly stimulated the immune response compared to control group. Researchers further evaluated the biological properties of the nanoparticles such as purity, solubility, stability by ultrafiltration and HPLC.
These preliminary data suggested that glycopeptides-bearing nanoparticles have the potential to be part of the repertoire of anti-metastasis, anticancer vaccine modalities that may have distinct and intriguing therapeutic utility.
Future Directions:
Strengths:
Weaknesses:
Patent Status:
US Application No. 10/578,385 filed Oct 27, 2004
PCT Application No. PCT/US2004/35831
Note: It is possible that an extension on the US patent life may be granted for any time delays by the USPTO
Publications:
Svarovsky SA et al. PMID: 14499569
Jayasekara PS et al. PMID: 23179047
Biswas S et al. PMID: 25556664
Brinãs RP et al. PMID: 22812418
Sundgren A et al. PMID: 18502409
Inventor Bio:
Dr. Barchi received his Ph.D. in Organic Chemistry from the University of Hawaii with Richard E. Moore and did 2 years of postdoctoral work at Duke University with Bert Fraser-Reid. He then joined the NCI as a staff fellow in 1988, was promoted to staff scientist and then to senior scientist in 2002. His main research interests are in synthetic medicinal chemistry as it relates to carbohydrate-based drug design, and the high-resolution structural analysis of sugars, glycopeptides and small molecule drug candidates by NMR spectroscopy.
Dr Barchi’s career at the NCI has spanned a wide breadth of drug discovery efforts, including the synthesis of PKC and reverse transcriptase inhibitors, the development of glycopeptide antigens as vaccine candidates against HIV and cancer, as well as the discovery of several glycopeptide-analogues of Antiproliferative Factor (APF), a negative growth factor isolated from patients with interstitial cystitis. Current focus in the lab is the discovery of novel nanoplatforms for the delivery and therapeutic applications of immunogenic glycopeptides, the search for selective antitumor agents based on APF and the conformational analysis of these synthetic analogues by NMR spectroscopy to guide further discovery efforts.
NIH Reference Number: E-001-2005
Executive Summary:
- Invention Type: Therapeutic
- Patent Status: Patent pending
- Link: https://www.ott.nih.gov/technology/e-001-2005
- NIH Institute or Center: National Cancer Institute (NCI)
- Disease Focus: Breast, colon, prostate, bladder, ovarian, gastric cancers, and pancreatic adenocarcinomas
- Basis of Invention: Glyconanoparticles consist of gold nanoparticles (AuNPs) coated with tumor-associated, cell-surface carbohydrate moiety
- How it works: Synthetic compounds consisting of carbohydrate tumor antigen are delivered to the tumor site by an AuNP carrier. The compound either masks or mimics the carbohydrate structure to inhibit the (Thomsen-Friedenreich) TF antigen-mediated, tumor-endothelial cell interactions, preventing tumor cell adhesion and metastasis
- Lead Challenge Inventor: Joseph Barchi (NCI)
- Inventors: Joseph Barchi (NCI), Sergei Svarovsky (NCI)
- Development Stage: Preclinical data is available, including in vitro biological characterization of glyconanoparticles. In vivo immunization data is also available in mouse models (groups of 20 mice) showing pharmacology and toxicity data of the compounds
-
Novelty:
- Specificity: Compounds include specific tumor-associated carbohydrates that are expressed only on the surface of tumor cells
- Versatility: Multifunctional nanoparticles may have distinct therapeutic utility
-
Clinical Applications:
- Anti-metastasis therapeutics
- Cancer vaccine
- Cancer imaging
- Other diseases such as viral/bacterial infections
General Description:
Tumor-associated carbohydrate antigens (TACA) are glycan chains expressed on the tumor cell surface, and rarely observed on the surface of the non-malignant cells. Fully processed, these carbohydrates on tumors lead to malignant cellular consequences such as modified cell adhesion, enhanced aggression, and metastasis.
Two widely distributed TACAs are Thomsen-Friedenreich (TF) disaccharide antigen and its corresponding “T nouvelle” (Tn) monosaccharide antigen. TF and Tn antigens are classic carbohydrate antigens that are shielded in healthy and benign-diseased tissues, but are uncovered in about 90% of carcinomas (e.g., breast, colon, prostate, bladder, ovarian, and gastric). The TF-bearing glycoproteins are believed to bind to carbohydrate-binding proteins on the surface of endothelial cells or shed from those site. This in turn repolarizes the tumor cell surface to expose other cell-adhesion molecules (e.g., integrins) to facilitate strong binding of the tumor cells to the endothelial surface leading to tumor cell colonization and metastasis. Scientists have been targeting these carbohydrate antigens to generate tumor-specific immunotherapy, or to inhibit the tumor-specific cell adhesion.
Cell surface glycan also plays important roles in the pathology of many other diseases such as inflammation, restenosis, bacterial/viral infections; therefore, the therapeutic could potentially be used for these indications.
Scientific Progress:
The researchers discovered an efficient way of preparing tumor antigen-containing glycopeptide building blocks from novel pentenyl glycosides. They further successfully synthesized TF-glycoamino acid conjugates attached to AuNP through a combined alkane/PEG linker, where the TF was attached to either a serine or threonine amino acid. TF-bound particles inhibited the growth of Galectin-3 positive tumor cells more significantly in vitro than that of the Galectin-3 negative tumor cells.
Recently, the researchers described the procedure of preparing a glyconanaoparticle that also contains peptides and linkers for cancer vaccination. The self-assembled particle was very stable and withstood repeated lysophilization and reconstitution. The molar ratio of the thiols used in the synthesis was 1:1:3 (MUC4 peptide/glycopeptide):(C3d peptide):(linker 6). In their study, the ligand coverage was estimated by calculating the particle surface area and the reactant concentration. They injected the vaccine particles into the mice (groups of 20), and tested the serum IgM and IgG level enzyme immunoassay afterwards. Vaccination significantly stimulated the immune response compared to control group. Researchers further evaluated the biological properties of the nanoparticles such as purity, solubility, stability by ultrafiltration and HPLC.
These preliminary data suggested that glycopeptides-bearing nanoparticles have the potential to be part of the repertoire of anti-metastasis, anticancer vaccine modalities that may have distinct and intriguing therapeutic utility.
Future Directions:
- Validation of the anti-metastasis functions of TACA-conjugated AuNP using in vivo animal models
- In vivo toxicity assay using an animal model
- Exploration of glycoparticles in cancer specific imaging
- Therapeutic intervention in other diseases such as HIV/AIDS where carbohydrate expression is involved in pathology
Strengths:
- Gold nanoparticles are easy to prepare and present a high degree of multivalency
- The size range of particles is easily controllable
- The particles exhibit low toxicity in vivo
- The inventor has actively continued to work and publish on the invention
- Versatility of the invention enables one to target orphan indications, leading to accelerated FDA approval
Weaknesses:
- Purification of multivalent AuNP conjugates could be challenging and requires condition optimization to maintain the biological activity of the conjugated ligands
- Glyconanaoparticles might exhibit different characteristics and behave differently when exposed to different solutions, hence the condition needs to be optimized during in vivo applications
Patent Status:
US Application No. 10/578,385 filed Oct 27, 2004
PCT Application No. PCT/US2004/35831
Note: It is possible that an extension on the US patent life may be granted for any time delays by the USPTO
Publications:
Svarovsky SA et al. PMID: 14499569
Jayasekara PS et al. PMID: 23179047
Biswas S et al. PMID: 25556664
Brinãs RP et al. PMID: 22812418
Sundgren A et al. PMID: 18502409
Inventor Bio:
Dr. Barchi received his Ph.D. in Organic Chemistry from the University of Hawaii with Richard E. Moore and did 2 years of postdoctoral work at Duke University with Bert Fraser-Reid. He then joined the NCI as a staff fellow in 1988, was promoted to staff scientist and then to senior scientist in 2002. His main research interests are in synthetic medicinal chemistry as it relates to carbohydrate-based drug design, and the high-resolution structural analysis of sugars, glycopeptides and small molecule drug candidates by NMR spectroscopy.
Dr Barchi’s career at the NCI has spanned a wide breadth of drug discovery efforts, including the synthesis of PKC and reverse transcriptase inhibitors, the development of glycopeptide antigens as vaccine candidates against HIV and cancer, as well as the discovery of several glycopeptide-analogues of Antiproliferative Factor (APF), a negative growth factor isolated from patients with interstitial cystitis. Current focus in the lab is the discovery of novel nanoplatforms for the delivery and therapeutic applications of immunogenic glycopeptides, the search for selective antitumor agents based on APF and the conformational analysis of these synthetic analogues by NMR spectroscopy to guide further discovery efforts.
