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Nano-Gold drugs developed using the GNTbm Vaucarrin® platform

 

The first generation of nano-gold anticancer drug --- Au/Dox

Doxorubicin (dox) is a commonly used chemotherapy agent. It is usually administered by intravenous injection and combined with other chemotherapy agents. Its half-life in the blood is only five minutes and it can be quickly distributed to tissues. Afterward, the drug can be still detected in the blood with a half-life of 20–48 hours, producing a three-phase half-life. Since the USFDA approval in 1974, doxorubicin has been used for more than 42 years and is still widely used in drug combinations for many cancer treatments. Using nano-gold and its bonded linker to deliver doxorubicin is the first generation of drugs developed by GNTbm; the combination will change the pharmacodynamics of doxorubicin in the body, effectively extend its half-life through the EPR effect of nano-drugs, deliver a high proportion of the drugs to tumor tissues, help to reduce the toxicity and side effects of doxorubicin, and enhance the efficacy. It is expected that the nano-gold drug will greatly decrease the doxorubicin dosage and improve its efficacy.

 

Au/Dox complex composition

AuNP
Doxorubicin
proprietary linker
PEG

Figure 9. Assembly of Au/Dox complex

Figure 10. The controlled-release bond between the Nano-Gold and the drug

Figure 11. Mechanisms of the delivery and controlled release of Au/Dox complex in tumor microenvironment

The second generation of nano-gold anticancer chemotherapy drug --- Au/Dox/Tras targeted nano-gold drug

Targeting helps to deliver nano-drugs to a specific target or diseased areas. Although the nano-drugs already have EPR effect that can greatly increase the drug accumulation in tumor or inflammatory tissues, it is a passive delivery mechanism. Increasing the targeting function of nano-drugs will increase the accuracy of drug delivery and reduce the off-target effects. This drug design has been named as an AGDC (Antibody-Gold-Drug Conjugate) by GNTbm. Upon the first generation of nano-gold drug complex, the binding of proprietary long-chain linkers conjugated with Trastuzumab is used as a targeting agent to identify breast cancer cells with high expression of HER-2 receptors; the binding of Trastuzumab with the HER-2 receptor leads to the intracellular phagocytosis of cancer cells, which results in the engulfment of the whole nano-gold drugs into cancer cells. In the lysosome, the nano-gold drug is decomposed to release doxorubicin and the accumulated high concentration of doxorubicin in the cancer cells then induces cancer cell apoptosis to achieve a therapeutic effect. The amount of trastuzumab in the targeted Au/Dox/Tras nano-gold drug is insufficient to exert its pharmacological activity, but sufficient to exert its targeting function; however, the amount of doxorubicin is sufficient to induce cancer cell apoptosis. Therefore, although the mechanism of AGDC drugs is similar to that of ADC (Antibody-Drug Conjugate), the difference is that ADC relies on highly toxic small molecules to kill cancer cells for therapeutic purposes.

 

Au/Dox/Tras Complex Composition

AuNP
Doxorubicin
Proprietary short-chain linker
Trastuzumab
Proprietary long-chain linker
PEG

Figure 12. Au/Dox/Tras complex

Figure 13. With the guidance of the Tras targeting antibody, the chemotherapy agent dox is delivered precisely to tumor cells

Advantages of AGDC nano-drugs

Drug loading ⇧
Targeting ⇧
Proprietary linkers control drug release Multiple loading of drugs or targeting molecules
Avoid off-targeting, resistance and side effect

Figure 14. AGDC drugs have both active and passive targeting properties that can deliver chemotherapy agents precisely to tumor cells

 

Au/ETA nano-gold protein drugs

Etanercept (ETA), a TNF inhibitor, was approved by the USFDA in 1998 for the treatment of rheumatoid arthritis. TNF-α is a pro-inflammatory factor, but is also a pivotal factor that controls the entire inflammatory response in rheumatoid arthritis. ETA is a highly effective biologic agent, but has a very short half-life, (approximately 70 hours) and needs to be self-administered subcutaneously by patients (25 mg per dose, twice per week). ETA is similar to a type of soluble-TNFα receptor and functions mainly through the removal of soluble-TNFα to reduce its binding with the TNF-α receptor on the surface of the inflammatory cells, which avoids triggering a series of inflammatory chain reactions and prevents the damage to bones and cartilage of the joint cavity that can eventually lead to joint deformation, disease progression, and cause deterioration of rheumatoid arthritis. The inflammatory joint cavity is similar to the tumor environment. Although the inflammation of ​​the joint cavity does not induce angiogenesis in the same way as tumors, vascular permeability is increased, which attracts many inflammatory blood cells and macrophages to migrate to the inflamed joint cavity. GNTbm believes that with an overall size of less than 100 nm, approximately 1/100th of the size of macrophages, a higher proportion of nano-gold may be delivered to this region through circulation and remain for a longer period. In addition, nano-gold can carry many ETA protein drug molecules on its surface, which can capture soluble-TNFα more efficiently than a single ETA protein drug and thereby increase the therapeutic effects.

 

Figure 15. Au/ETA complex

Figure 16. Assembly of Au/ETA complex

Figure 17. The possible delivery mechanism of Au/ETA complex in inflamed joint cavity