Cancer Therapy with Nanobody-Drug Conjugates

Chemotherapy, although widely employed in cancer treatment, is accompanied by significant side effects. Antibody-drug conjugates (ADCs) have shown promising therapeutic effects, but their large molecular weight restricts tissue penetration. Consequently, nanobody-drug conjugates (NDCs) have garnered considerable attention due to their rapid clearance, high stability, and enhanced tumor penetration.

Mechanism of Action of NDCs

NDCs specifically target cancer sites in vivo, binding to cancer antigens through nanobodies and internalizing via receptor-mediated endocytosis. Upon internalization, the drug is released into the cytoplasm, interfering with DNA or inhibiting enzyme activity, ultimately leading to cancer cell apoptosis.

Target Selection

The selection of cancer biomarkers/antigens is based on their expression levels, accessibility, and subcellular transport mechanisms. These targets play a pivotal role in novel NDC or nanobody-drug vector (NDv) therapies.

NDC Conjugation Strategies

Drug Types: NDC drugs are primarily classified as DNA-damaging agents and microtubule inhibitors.

Linker Properties: Linkers must possess high stability and self-cleaving capabilities, while also considering stability, hydrophobicity, and cleavable or non-cleavable properties.

Drug-to-Antibody Ratio: The robustness of nanobodies (Nbs) facilitates their easier entry into target cells.

Site-Specific Conjugation: Utilizing the natural amino acid active sites of Nbs for conjugation, such as cysteine and lysine, new tools like lysine amide conjugation and cysteine residue insertion are employed to achieve uniform mixtures.

Advances in NDv Research

NDv uses nanobodies to modify nanocarriers, boosting drug loading and minimizing side effects. Polymeric micelles, dendrimers, and liposomes show anticancer potential. Liposomes with anti-EGFR nanobodies downregulate EGFR, inhibiting cancer cell growth. NDv's precise targeting makes it a promising chemotherapy alternative.

Types of Carriers for NDC or NDv

Polymeric Micelles: Nanoscale, biocompatible, stable, solubilized insoluble drugs. Enhance target site accumulation with anti-EGFR nanobodies, show bioimaging properties, and inhibit tumor growth.

Dendrimers: Radially symmetric, high biocompatibility, multivalent surface. Clustered NDCs (cNDCs) have longer half-life, stronger anticancer efficiency, and greater tumor accumulation.

Liposomes: Spherical, composed of phospholipids and cholesterol. Selectively recognize and downregulate EGFR with anti-EGFR nanobodies, leading to EGFR degradation and inhibiting rapidly proliferating cancer cells. Less effective in slowly growing cancer cells.

Conclusion

The creation of NDCs or NDvs offers attractive strategies to overcome the limitations of chemotherapy. Compared to monoclonal antibodies, nanobodies exhibit higher recognition efficiency and fewer side effects. As research progresses, nanobody-based drug discovery and therapeutic methods will gradually translate into practical applications, bringing new hope for cancer treatment.

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