Selective CXCR4⁺ Cancer Cell Targeting and Potent Antineoplastic Effect by a Nanostructured Version of Recombinant Ricin

Abstract

Under the unmet need of efficient tumor-targeting drugs for oncology, a recombinant version of the plant toxin ricin (the modular protein T22-mRTA-H6) is engineered to self-assemble as protein-only, CXCR4-targeted nanoparticles. The soluble version of the construct self-organizes as regular 11 nm planar entities that are highly cytotoxic in cultured CXCR4 cancer cells upon short time exposure, with a determined IC50 in the nanomolar order of magnitude. The chemical inhibition of CXCR4 binding sites in exposed cells results in a dramatic reduction of the cytotoxic potency, proving the receptor-dependent mechanism of cytotoxicity. The insoluble version of T22-mRTA-H6 is, contrarily, moderately active, indicating that free, nanostructured protein is the optimal drug form. In animal models of acute myeloid leukemia, T22-mRTA-H6 nanoparticles show an impressive and highly selective therapeutic effect, dramatically reducing the leukemia cells affectation of clinically relevant organs. Functionalized T22-mRTA-H6 nanoparticles are then promising prototypes of chemically homogeneous, highly potent antitumor nanostructured toxins for precise oncotherapies based on self-mediated intracellular drug delivery.

A CXCR4-targeted nanocarrier achieves highly selective tumor uptake in diffuse large B-cell lymphoma mouse models

“…We have previously described also the potential use of T22-GFP-H6 as an antitumor drug delivery agent for the treatment of colorectal cancer and leukemia. 18,38,39 To our knowledge, no protein-based therapeutic nanoparticle has been previously reported as a possible drug carrier for lymphoma therapy.…”

Ricin and Ricinus communis in pharmacology and toxicology-from ancient use and “Papyrus Ebers” to modern perspectives and “poisonous plant of the year 2018”

“…Finally, a most recent study engineered CXCR4-targeted nanoparticles via self-assembly of the modular protein T22-mRTA-H6, a recombinant version of ricin. Beyond high cytotoxicity in CXCR4+ tumor cells in vitro, profound therapeutic anti-tumor activity in the absence of toxic side effects was also observed in a mouse model of acute myeloid leukemia (Diaz et al 2018).…”

Engineering of Ribosome-inactivating Proteins for Improving Pharmacological Properties

“…Vascular leak syndrome is a major side effect of many RIP-based ITs. Ricin and T22, a ligand of the cell surface marker C-X-C motif chemokine receptor type 4 (CXCR-4), were assembled to form nanostructures, which exhibited specific anti-tumor activity and avoided VLS [98].…”