Application of activated nucleoside analogs for the treatment of drug-resistant tumors by oral delivery of nanogel-drug conjugates

Abstract

A majority of nanoencapsulated drugs that have shown promise in cancer chemotherapy are administered intravenously. Development of effective oral nanoformulations presents a very challenging medical goal. Here, we describe successful applications of innovative polymeric nanogels in the form of conjugates with activated nucleoside analogs for oral administration in cancer chemotherapy. Previously, we reported the synthesis of amphiphilic polyvinyl alcohol and dextrin-based nanogel conjugates with the phosphorylated 5-FU nucleoside Floxuridine and demonstrated their enhanced activity against regular and drug-resistant cancers[1]. In this study, we synthesized and evaluated oral applications of nanogel conjugates of a protected Gemcitabine, the drug never used in oral therapies. These conjugates were able to quickly release an active form of the drug (Gemcitabine 5′-mono-, di- and triphosphates) by specific enzymatic activities, or slowly during hydrolysis. Gemcitabine conjugates demonstrated up to 127 times higher in vitro efficacy than the free drug against various cancer cells, including the lines resistant to nucleoside analogs. Surprisingly, these nanogel-drug conjugates were relatively stable in gastric conditions and able to actively penetrate through the gastrointestinal barrier based on permeability studies in Caco-2 cell model. In tumor xenograft models of several drug-resistant human cancers, we observed an efficient inhibition of tumor growth and extended the life-span of the animals by 4 times that of the control with orally treated Gemcitabine- or Floxuridine-nanogel conjugates. Thus, we have demonstrated a potential of therapeutic nanogel conjugates with the activated and stabilized Gemcitabine as a successful oral drug form against Gemcitabine-resistant and other drug-resistant tumors.

Bioavailability enhancement, Caco-2 cells uptake and intestinal transport of orally administered lopinavir-loaded PLGA nanoparticles

“…where dQ/dt -the amount of NPs/drug in basolateral compartment as a function of time (mg/min), A -the monolayer area (cm 2 ), C 0 -the initial concentration of NPs/ drug in apical compartment (mg/mL) (Senanayake et al, 2013). Here, the initial drug concentration was 0.2 mg/ml, area was 1.13 cm 2 .…”

Preparation and evaluation of chitosan-based nanogels/gels for oral delivery of myricetin

“…However, the poor solubility or instability of many drug candidates in the gastrointestinal (GI) fluid decreases the gastric residence time and consequently lead to the low bioavailability after oral administration (Karnoosh-Yamchi et al, 2014;Qi et al, 2015;Senanayake et al, 2013).…”

“…For instance, nanogel conjugates of gemcitabine were relatively stable in gastric conditions and were able to actively penetrate through the gastrointestinal barrier, which possibly resulted from an increased GI adsorption (Senanayake et al, 2013). Furthermore, the anti-norovirus activity of interferons (IFN) showed a steep drop (by 80%) in PBS in 3 days of incubation at 4°C, while the activity of IFN-loaded nanogels decreased only by up to 17% during the same period.…”

Amphiphilic Cationic Nanogels as Brain-Targeted Carriers for Activated Nucleoside Reverse Transcriptase Inhibitors

“…Exocyclic amino group of Lamivudine was protected by isobutyryl moiety using a transient protection by trimethylsilyl moiety (Senanayake et al 2013). Each nucleoside analog dissolved in dry dimethylformamide (DMF) was treated with a 1.5-molar excess of tris -triazolyl phosphate reagent for 30–60 min at 4°C, and then added dropwise to the excess of tri-n-butylammonium pyrophosphate in dry DMF.…”