Vorinostat–Polymer Conjugate Nanoparticles for Acid-Responsive Delivery and Passive Tumor Targeting

Abstract

In vivo histone deacetylase (HDAC) inhibition by vorinostat under clinically acceptable dosing is limited by its poor pharmacokinetics properties. A new type of nontoxic pH-responsive delivery system has been synthesized by ring-opening metathesis polymerization, allowing for the selective distribution of vorinostat in mesothelioma tumors in vivo and subsequent histone reacetylation. The delivery system is synthesized by generic click chemistry, possesses native stealth properties for passive tumor targeting, and does not need additional chemistry for cellular internalization. Although vorinostat alone at 50 mg/kg in mice showed no effect, our new delivery system with 2 mg/kg vorinostat promoted histone reacetylation in tumors without side effects, demonstrating that our strategy improves the activity of this HDAC inihibitor in vivo.

Biodegradable Polysaccharides for Controlled Drug Delivery

“…Various biomolecular moieties such as bile acids, natural amphiphilic steroids, or lauryl chains have been grafted onto dextran . Chemically modified, azido‐bearing dextran nanoparticles have been conjugated with mannose groups and exhibited enhanced antigen response due to internalization and activation of antigen‐presenting cells . Acrylic acid was grafted onto dextran to produce pH‐sensitive nanoparticles ranging in size from 40 to 140 nm.…”

A facile route to form self-carried redox-responsive vorinostat nanodrug for effective solid tumor therapy

“…Both SAHA-S-S-VE and SAHA-S-S-VE/TPGS NPs showed enhanced antiproliferative activities (lower IC 50 values) compared with free SAHA in all the tested cell lines, whereas the NH 2 -S-S-VE showed little toxicity in the given concentration range after 48 h. Among these four cell lines, SAHA-S-S-VE/TPGS NPs revealed the most obvious antiproliferative activity (P,0.01, compared to free SAHA) in HepG2 cell line. The enhanced cytotoxic might be due to one or two of the following mechanisms: 1) the lipophilic nature of SAHA-S-S-VE (higher log P; Table 2) might facilitate intracellular uptake 11,14,51 and 2) when the concentration of SAHA-S-S-VE/TPGS NPs was higher than the CAC, part of the self-assembled SAHA-S-S-VE/TPGS NPs might keep intact for the low GSH concentration in the cell culture medium, 38 which resulted in the greater cellular uptake through the endocytic pathway and higher cytotoxic efficiency. 1 Besides, the GSH-insensitive SAHA-O-VE appeared to have a significantly lower proliferation inhibitory efficacy than SAHA-S-S-VE, which might be resulted from the slow release of SAHA.…”

“…Recently, SAHA-polymer conjugate NPs constructed by Blanquart et al showed good effect toward malignant mesothelioma by passive tumor targeting. 14 Inspired by these, self-assembled SAHA prodrug can not only take the advantage of nanoscale drug delivery system but also increase the drug loading capacity dramatically.…”

Nanoparticulate immunotherapy for cancer

“…These carriers have improved vorinostat solubility up to 40-fold, improved the pharmacokinetics, extended circulation half-life, and decreased clearance [140,141]. Furthermore, the therapeutic index of vorinostat was improved by developing acid sensitive delivery system out of a pro-drug of vorinostat [142]. Moreover, it was discovered that epigenetic drugs can sensitize tumors to chemotherapy to enhance their efficacy.…”