Cytotoxic drug bundles

A cytotoxic drug bundle is a packed multi-arm linker carrying multiple molecules of a small molecular cytotoxic drug.

The linking arms used in a cytotoxic drug bundle can be optionally designed to contain a cleavable site so that the drug molecules can be cleaved off at the targeted tissues or in the targeted cells. Such a cleavable site is sensitive to an enzyme rich in microenvironment of the targeted tissue or in the endosomes/lysosomes of the targeted cells.  

A host of potent cytotoxic drugs such as mertansine (DM1), monomethyl auristatin E (MMAE), and pyrrolobenzodiazepines (PBD), immunomodulatory drugs (IMiDs) such as lenalidomide (Lena), are applicable for preparing cytotoxic drug bundles.

A coupling arm equipped with a functional group for click reaction, such as dibenzocyclooctyne (DBCO), trans-cyclooctene (TCO), or maleimide group, for the conjugation with an antibody molecule.

The aqueous solubility of the drug bundles can be adjusted by varying the compositions of the core and linking and coupling arms.

Typically, a maleimide group and adjacent acidic amino acid residues are installed at the end of coupling arm. The cluster of negative charges potentiate the maleimide group as an electrophile.

Here is an example of a cytotoxic drug bundle.

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