Novel Anticancer Polymeric Conjugates of Activated Nucleoside Analogues

Abstract

Inherent or therapy-induced drug resistance is a major clinical setback in cancer treatment. The extensive usage of cytotoxic nucleobases and nucleoside analogs in chemotherapy also results in the development of specific mechanisms of drug resistance; such as nucleoside transport or activation deficiencies. These drugs are prodrugs; and being converted into the active mono-, di- and triphosphates inside cancer cells following administration, they affect nucleic acid synthesis, nucleotide metabolism, or sensitivity to apoptosis. Previously, we have actively promoted the idea that the nanodelivery of active nucleotide species, e.g. 5′-triphosphates of nucleoside analogs, can enhance drug efficacy and reduce nonspecific toxicity. In this study we report the development of a novel type of drug nanoformulations, polymeric conjugates of nucleoside analogs, which are capable of the efficient transport and sustained release of phosphorylated drugs. These drug conjugates have been synthesized, starting from cholesterol-modified mucoadhesive polyvinyl alcohol or biodegradable dextrin, by covalent attachment of nucleoside analogs through a tetraphosphate linker. Association of cholesterol moieties in aqueous media resulted in intramolecular polymer folding and the formation of small nanogel particles containing 0.5 mmol/g of a 5′-phosphorylated nucleoside analog, e.g. 5-fluoro-2′-deoxyuridine (floxuridine, FdU), an active metabolite of anticancer drug 5-fluorouracyl (5-FU). The polymeric conjugates demonstrated rapid enzymatic release of floxuridine 5′-phosphate and much slower drug release under hydrolytic conditions (pH 1.0–7.4). Among the panel of cancer cell lines, all studied polymeric FdU-conjugates demonstrated an up to 50 times increased cytotoxicity in human prostate cancer PC-3, breast cancer MCF-7 and MDA-MB-231 cells, and more than 100 times higher efficacy against cytarabine-resistant human T-lymphoma (CEM/araC/8) and gemcitabine-resistant follicular lymphoma (RL7/G) cells as compared to free drugs. In the initial in vivo screening, both PC-3 and RL7/G subcutaneous tumor xenograft models showed enhanced sensitivity to sustained drug release from polymeric FdU-conjugate after peritumoral injections and significant tumor growth inhibition. All these data demonstrate a remarkable clinical potential of novel polymeric conjugates of phosphorylated nucleoside analogs, especially as new therapeutic agents against drug-resistant tumors.

Nanogel-Conjugated Reverse Transcriptase Inhibitors and Their Combinations as Novel Antiviral Agents with Increased Efficacy against HIV-1 Infection

“…For example, we recently developed nanogel-nucleoside analog conjugates with polyphosphate linker that was stable even after oral administration. 34 NRTI prodrugs based on cationic ε -polylysine are inexpensive and can be obtained using simple synthetic procedures. We also anticipate potential application of PEG-CEPL-sNRTI nanodrugs for more efficient therapy of HIV-1 infection in the CNS.…”

Synthesis and in vitro evaluation of bile acid prodrugs of floxuridine to target the liver

“…Floxuridine conjugates of peptides have been synthesized to target peptide transporter 1 (PEPT1, SLC15A1 ) with the objective of increasing oral bioavailability, lowering variability in uptake, and preventing conversion to 5-FU by TP (10, 11). Additionally, polymer conjugates of its active triphosphate form have been synthesized (12), as well as phosphoactivated (13), phosphoramidated (14), and alkyl ester (15, 16) forms of floxuridine prodrugs. These prodrugs aim to enhance floxuridine bioavailability and to promote its tumor-specific delivery, thus reducing non-specific toxicity.…”

Encapsulation of Poorly Soluble Drugs in Polymer-Drug Conjugates: Effect of Dual-Drug Nanoformulations on Cancer Therapy

“…We previously demonstrated that nanogel-drug conjugates (nanodrugs) of floxuridine and gemcitabine are efficient against regular and drug-resistant tumors (11, 12). The nanodrugs containing nucleoside analogs attached via the tetraphosphate linker to CPVA demonstrated strong tumor growth inhibition activity even against drug-resistant cancers.…”