Drug-Initiated Synthesis of Heterotelechelic Polymer Prodrug Nanoparticles for in Vivo Imaging and Cancer Cell Targeting

Abstract

Drug-initiated" nitroxide-mediated synthesis of two well-defined, heterotelechelic polymer prodrugs (M n = 1960-5260 g.mol-1 , Đ = 1.31-1.37) was performed by using the newly-developed nitroxide exchange reaction. These polymers comprised at the chain-end, gemcitabine (Gem) as anticancer drug and either cyanine 7.5 (Cy7.5) as a near-infrared (NIR) dye suitable for in vivo imaging, or biotin (Biot) for cancer cell targeting. These materials were co-nanoprecipitated into fluorescently-labeled polymer prodrug nanoparticles of average diameter in the 100-180 nm with narrow particle size distribution and variable surface amounts of biotin. Nanoparticles containing 15 wt.% biotinylated polymer showed superior uptake and the highest cytotoxicity in vitro on A549 human lung cancer cells. In vivo, on A549 tumor bearing mice, biotinylated nanoparticles showed significantly higher efficacy than free Gem and maintained the same anticancer activity than nontargeted nanoparticles without inducing prohibitive body weight loss. Biotinylated polymer prodrug nanoparticles did not result in an improved anticancer activity or significant increase in tumor accumulation, which may be the result of either a not optimal biotin surface display and/or insufficient affinity towards the target. They however displayed delayed liver accumulation compared to non-biotinylated counterparts, suggesting premise of stealth property likely due to the hydrophilic tetraethyleneglycol-Biot positioned at the nanoparticle surface. This work showed for the first time the applicability of this simple construction method to in vivo imaging and cancer cell targeting, and might stimulate the design of new functional materials for biomedical applications.

Resveratrol and its Nanoparticle suppress Doxorubicin/Docetaxel-resistant anaplastic Thyroid Cancer Cells in vitro and in vivo

“…V (mm 3 ) is tumor volume, A (mm) is tumor length, B (mm) is tumor width. The percentage of tumor volume change = (tumor volume on the day of measurement -tumor volume at day 0) / tumor volume at day 0 * 100%, and the first day of administration is recorded as day 0 [37]. Euthanasia was conducted if the weight loss of tumor-bearing nude mice is close to 15% [38].…”

Nitroxide-Mediated Polymerization: A Versatile Tool for the Engineering of Next Generation Materials

“…170 The group has since demonstrated that this technique is effective at producing heterotelechelic polymer prodrugs by coupling PI polymer with gemcitabine/lapatinib (Gem/Lap), gemcitabine/doxorubicin (Gem/Dox) 180 and combining Gem and cyanine 7.5 (Cy7.5), a near-infrared dye for in vivo imaging, or Gem and biotin (Biot) for cancer cell targeting. 181 The authors further developed this "druginitiated" NMP technique to synthesize a polymer containing a neuroprotective drug (adenosine) and a maleimide functional group, which formed nanoparticles that were then surface-modified with proteins to target and cross the bloodbrain barrier (BBB), including albumin (BSA), α2-macroglobulin (α2M) and fetuin A (Fet A). 182 All nanoparticles formed were stable with narrow particle size distributions, and α2 M enhanced the passage through the BBB in an in vitro model, making this a promising strategy for BBB-targeted drug delivery.…”

Recent Trends in In Situ Enzyme-Activatable Prodrugs for Targeted Cancer Therapy

“…For this reason, the DT-diaphorase-activatable camptothecin prodrug adopted biotin as a tumor-targeting ligand (Figure c) . Another example was the polymer prodrug of gemcitabine (Gem) and Cy7.5, recently developed by Vinciguerra et al, who introduced biotin moiety as a targeting ligand …”

“…54 Another example was the polymer prodrug of gemcitabine (Gem) and Cy7.5, recently developed by Vinciguerra et al, who introduced biotin moiety as a targeting ligand. 82 RGD (Arg-Gly-Asp) peptide is also a popular targeting ligand. Previously, Chung et al conjugated the caspaseactivatable DOX prodrug to RGD peptide to target the integrin αvβ3 receptor, which was overexpressed in cancer.…”