Gram Scale Synthesis of Dual-Responsive Dendritic Polyglycerol Sulfate as Drug Delivery System

Abstract

Biocompatible polymers with the ability to load and release a cargo at the site of action in a smart response to stimuli have attracted great attention in the field of drug delivery and cancer therapy. In this work, we synthesize a dual-responsive dendritic polyglycerol sulfate (DR-dPGS) drug delivery system by copolymerization of glycidol, ε-caprolactone and an epoxide monomer bearing a disulfide bond (SSG), followed by sulfation of terminal hydroxyl groups of the copolymer. The effect of different catalysts, including Lewis acids and organic bases, on the molecular weight, monomer content and polymer structure was investigated. The degradation of the polymer backbone was proven in presence of reducing agents and candida antarctica Lipase B (CALB) enzyme, which results in the cleavage of the disulfides and ester bonds, respectively. The hydrophobic anticancer drug Doxorubicin (DOX) was loaded in the polymer and the kinetic assessment showed an enhanced drug release with glutathione (GSH) or CALB as compared to controls and a synergistic effect of a combination of both stimuli. Cell uptake was studied by using confocal laser scanning microscopy with HeLa cells and showed the uptake of the Dox-loaded carriers and the release of the drug into the nucleus. Cytotoxicity tests with three different cancer cell lines showed good tolerability of the polymers of as high concentrations as 1 mg mL−1, while cancer cell growth was efficiently inhibited by DR-dPGS@Dox.

Hyaluronic Acid–Zein Core-Shell Nanoparticles Improve the Anticancer Effect of Curcumin Alone or in Combination with Oxaliplatin against Colorectal Cancer via CD44-Mediated Cellular Uptake

“…Equivalent doses of HZ did not significantly affect CRC cell growth. Similarly, the enhanced cytotoxicity of hydrophobic anticancer drug doxorubicin was achieved with a dual-responsive dendritic polyglycerol sulfate delivery system [ 28 ]. CUR and HZ-CUR at 4 μg/mL (<IC 50 ) were subsequently selected to assess their potential synergistic effects with OXA ( Figure 2 D–F).…”

Power of the Disulfide Bond: An Ideal Random Copolymerization of Biodegradable Redox-Responsive Hyperbranched Polyglycerols

“…44,45 Moreover, the reaction was performed strictly at 70 °C, as the disulfide bond decomposes at higher temperatures. 28,29 DPP, a Brønsted acid with a pK a of 3.88 in DMSO, 46 was the catalyst of choice since it was proven to have an effective catalytic activity for the polymerization of OTP while avoiding undesirable nucleophilic attack on the disulfide bond, in comparison to other Lewis and Brønsted catalysts. 32 The reactivity ratios (r i, i = 1 for Gly and i = 2 for OTP or CL), which are defined as (r 1 = k 11 /k 12 , the rate of homopolymerization of the comonomer over the rate of copolymerization), were then calculated according to the Mayo−Lewis, 47 Fineman−Ross, 48 and Kelen−Tudos 49 approaches.…”

Polyglycerols as Multi-Functional Platforms: Synthesis and Biomedical Applications

“…TAC has low bioavailability, and the system was proven to load TAC effectively (14.5% w/w loading capacity) and ensure its educated delivery into the stratum corneum, viable epidermis, and upper epidermis when compared with Protopic ®® (containing 0.03% w/w of TAC) [51]. On the other hand, Reisbeck et al, developed an HPG sulfates drug delivery system that was dual degradable based on the copolymerization of glycidol, ε-caprolactone, and SSG, the glycidol derivative monomer bearing a disulfide bond in bulk screening different catalysts [52]. The catalyst that was most prominent for polymerization was strontium isopropoxide, leading to the highest molecular weight and degree of branching [52].…”

“…On the other hand, Reisbeck et al, developed an HPG sulfates drug delivery system that was dual degradable based on the copolymerization of glycidol, ε-caprolactone, and SSG, the glycidol derivative monomer bearing a disulfide bond in bulk screening different catalysts [52]. The catalyst that was most prominent for polymerization was strontium isopropoxide, leading to the highest molecular weight and degree of branching [52]. The system was degradable under enzymatic and reductive stimuli and was capable of encapsulating and releasing doxorubicin under the same conditions [52].…”

“…The catalyst that was most prominent for polymerization was strontium isopropoxide, leading to the highest molecular weight and degree of branching [52]. The system was degradable under enzymatic and reductive stimuli and was capable of encapsulating and releasing doxorubicin under the same conditions [52].…”