Combretastatin A-4 Conjugated Antiangiogenic Micellar Drug Delivery Systems Using Dendron–Polymer Conjugates

Abstract

Employment of polymeric nanomaterials in cancer therapeutics is actively pursued since they often enable drug administration with increased efficacy along with reduced toxic side effects. In this study, drug conjugated micellar constructs are fabricated using triblock dendron-linear polymer conjugates where a hydrophilic linear polyethylene glycol (PEG) chain is flanked by well-defined hydrophobic biodegradable polyester dendrons bearing an antiangiogenic drug, combretastatin-A4 (CA4). Variation in dendron generation is utilized to obtain a library of micellar constructs with varying sizes and drug loadings. In particular, a family of drug appended dendron-polymer conjugates based on polyester dendrons of generations ranging from G1 to G3 and 10 kDa linear PEG were obtained using [3 + 2] Huisgen type "click" chemistry. The final constructs benefit from PEG's hydrophilicity and antibiofouling character, as well as biodegradable nature of the hydrophobic polyester dendrons. The hydrophobic-hydrophilic-hydrophobic character of these constructs leads to the formation of flower-like micelles in aqueous media. In addition to generation-dependent subnanomolar range critical micelle concentrations, the resulting micelles possess hydrodynamic diameters suitable for passive tumor targeting through enhanced permeability and retention (EPR) effect; thereby they are suitable candidates as controlled drug delivery agents. For all constructs, in vitro cytotoxicities were investigated and inhibitory effect of Comb-G3-PEG on tube formation was shown on human umbilical vein endothelial cells (HUVECs).

MRI Monitoring of Cerebral Blood Flow after the Delivery of Nanocombretastatin across the Blood Brain Tumor Barrier

“…The 1 H-NMR spectrum Figure 1B showed multiplets between δ 1.0 and 4.0 ppm corresponding to the presence of -CH and -CH 2 protons from G3-PAMAM-succinamic acid and CA4. The peaks between δ 6.4 and 8.4 ppm correspond to the presence of hydrogen atoms on the phenyl rings in CA4 [37]. The peak at δ 8.9 ppm in CA4 that corresponds to -OH is absent in the resulted G3-CA4 conjugated product due to the conjugation with G3-succinamic acid dendrimer.…”

Drug Delivery Systems from Self-Assembly of Dendron-Polymer Conjugates †

“…Sanyal and coworkers used an ABA type dendron-polymer-dendron conjugate with 10 kDa middle PEG segment connecting two identical polyester dendrons with generation 1–3. The dendron surfaces were further modified with combretastatin-A4 anti-angiogenic drug ( Scheme 9 ) [ 91 ]. Size and CMC values of prepared Comb-Gx-PEG and Gx-PEG micelles displayed dendron generation and drug content related trends.…”

Design and Synthesis of ZnII‐Coordination Polymers Anchored with NSAIDs: Metallovesicle Formation and Multi‐drug Delivery

“…When a drug is administered, it has to face many obstacles (such as rapid degradation and excretion due to immune response of the biological system) before it can reach the target site; to overcome such obstacles, various drug delivery vehicles (such as vesicles, polymer gel matrix, reverse micelles, etc.) are being developed.…”