Modular transporters for subcellular cell‐specific targeting of anti‐tumor drugs

Abstract

A major problem in the treatment of cancer is the specific targeting of anti-tumor drugs to these abnormal cells. Ideally, such a drug should act over short distances to minimize damage to healthy cells, and target subcellular compartments that have the highest sensitivity to the drug. Photosensitizers, alpha-emitting radionuclides and many other medicines could be considered as such drugs if they possessed cellular and subcellular specificity. The author describes a novel approach of using modular recombinant transporters to target photosensitizers and alpha-emitting radionuclides to the nucleus, where their action is most pronounced, of cancer cells. Photosensitizer-transporter conjugates have up to 3000 times greater efficacy than free photosensitizers and display cell specificity in contrast to free photosensitizers. Alpha-emitting radionuclides, conjugated with the modular transporters, acquired similar properties. The different modules of the transporters are interchangeable, meaning that they can be tailored for particular applications.

Preparation, cytotoxicity, and in vivo antitumor efficacy of ¹¹¹In-labeled modular nanotransporters

“…30,31 Because nuclear import machinery resides in the cytoplasm, the MNT must escape the endosomes before its NLS component can activate nuclear transport. This is accomplished by its endosomolytic module, which increases its hydrophobicity to provide penetration through the endosomal membrane in response to the decreased pH of acidifying endosomes.…”

Nanodrug applications in photodynamic therapy

“…Such an approach offers the potential to achieve better subcellular targeting. A good example is the modular recombinant transporter approach described by Sobolev [182]. Although complex systems, they allow a targeting of the cancer tissue and the most susceptible intracellular compartment, the nucleus.…”

Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery

“…Pursuing this strategy, 13 we designed, produced, and characterized bacterially-expressed MNT comprising α-melanocyte-stimulating hormone (αMSH) or epidermal growth factor (EGF) for targeting αMSH receptors that are overexpressed in melanoma 14 or the epidermal growth factor receptor (EGFR) that is overexpressed on several cancers, including head and neck, breast carcinoma, and glioblastoma, 15 the optimized nuclear localization sequence from SV40 large tumor antigen, the Escherichia coli hemoglobinlike protein (HMP) as a carrier module, and a translocation domain of diphtheria toxin as the endosomolytic amphipathic module (DTox). Having demonstrated that MNT could be produced and purified efficiently, with retention of function of each of the modules, and having shown that every module is necessary for the maximum MNT activity, 12,16 we next evaluated their potential utility as a platform for targeted cancer therapy.…”