Cell-Penetrating, Guanidinium-Rich Molecular Transporters for Overcoming Efflux-Mediated Multidrug Resistance

Abstract

Multidrug resistance (MDR) is a major cause of chemotherapy failure in the clinic. Drugs that were once effective against naïve disease subsequently prove ineffective against recurrent disease, which often exhibits an MDR phenotype. MDR can be attributed to many factors; often dominating among these is the ability of a cell to suppress or block drug entry through upregulation of membrane-bound drug efflux pumps. Efflux pumps exhibit polyspecificity, recognizing and exporting many different types of drugs, especially those whose lipophilic nature contributes to residence in the membrane. We have developed a general strategy to overcome efflux-based resistance. This strategy involves conjugating a known drug that succumbs to efflux-mediated resistance to a cell-penetrating molecular transporter, specifically, the cell-penetrating peptide (CPP), d-octaarginine. The resultant conjugates are discrete single entities (not particle mixtures) and highly water-soluble. They rapidly enter cells, are not substrates for efflux pumps, and release the free drug only after cellular entry at a rate controlled by linker design and favored by target cell chemistry. This general strategy can be applied to many classes of drugs and allows for an exceptionally rapid advance to clinical testing, especially of drugs that succumb to resistance. The efficacy of this strategy has been successfully demonstrated with Taxol in cellular and animal models of resistant cancer and with ex vivo samples from patients with ovarian cancer. Next generation efforts in this area will involve the extension of this strategy to other chemotherapeutics and other MDR-susceptible diseases.

Taking the vehicle out of drug delivery

“…Although metformin is clinically approved for the treatment of diabetes, this drug has shown promise as an anticancer agent in multiple clinical trials. Moreover, metformin contains guanidine groups, which have previously been shown to increase cellular uptake, enhance transfection, and circumvent efflux pumps [3]. PolyMet was synthesized through the conjugation of linear polyethylenimine (PEI) with dicyandiamide.…”

“…Specifically, polymeric metformin serves both as a therapeutic agent and carrier for siRNA. As a delivery component, polymeric metformin provides siRNA protection and efficient transfection, partially due to the presence of guanidine groups in the drug, which have been found to traverse cell membranes and tissue barriers [3]. It has been speculated that guanidine is able to penetrate the cell membrane by forming a bidentate hydrogen bond with cell surface groups, such as phosphates, carboxylates, and sulfates [3].…”

Linker design for the modular assembly of multifunctional and targeted platinum(ii)-containing anticancer agents

“…26 The arginine derivative N4 was introduced as a model of amino acids and oligopeptides that might potentially facilitate uptake of platinum–(benz)acridines into cancer cells. 27 Multifunctional conjugates containing other clinically approved drugs or their key pharmacophores targeted at specific forms of cancer were also generated. The amine components introduced include (i) rucaparib 28 (Clovis Oncology) ( N5 ), a member of the class of poly-ADP-ribose polymerase-1 (PARP-1) inhibitors, which have been shown to sensitize cancer cells to DNA-targeted chemotherapies, 29 (ii) endoxifen ( N6 ), the active form of the estrogen receptor (ER) antagonist and breast cancer treatment tamoxifen, 30 and (iii) the epidermal growth factor receptor (EGFR) kinase-targeted quinazoline-based inhibitor N7 , 31 a derivative of the lung cancer therapy gefitinib (Astra Zeneca).…”

Butorphanol, a synthetic opioid, sensitizes ABCB1-mediated multidrug resistance via inhibition of the efflux function of ABCB1 in leukemia cells

“…moreover, there is no effective therapy for patients with relapse (23). MDR has been known as the mainly contributing factor to treatment failure, and its involvement has become a primary cause of mortality and a formidable impediment to achieving long-term remission in leukemia (24). The universally recognized mechanism of mDR may be the overexpression of ABC transporters which can weaken the cytotoxic effect of chemotherapeutic agents via transferring drugs to the cell exterior (25).…”