Designing Dendron–Polymer Conjugate Based Targeted Drug Delivery Platforms with a “Mix-and-Match” Modularity

Abstract

Polymeric micellar systems are emerging as a very important class of nanopharmaceuticals due to their ability to improve pharmacokinetics and biodistribution of chemotherapy drugs, as well as to reduce related systemic toxicities. While these nanosized delivery systems inherently benefit from passive targeting through the enhanced permeation and retention effect leading to increased accumulation in the tumor, additional active targeting can be achieved through surface modification of micelles with targeting groups specific for overexpressed receptors of tumor cells. In this project, nontoxic, biodegradable, and modularly tunable micellar delivery systems were generated using two types of dendron-polymer conjugates. Either an AB type dendron-polymer construct with 2K PEG or an ABA type dendron-polymer-dendron conjugate with 6K PEG based middle block was used as primary construct; along with an AB type dendron-polymer containing a cRGDfK targeting group to actively target cancer cells overexpressing αβ/αβ integrins. A set of micelles encapsulating docetaxel, a widely employed chemotherapy drug, were prepared with varying feed ratios of primary construct and targeting group containing secondary construct. Critical micelle concentrations of all micellar systems were in the range of 10 M. DLS measurements indicated hydrodynamic size distributions varying between 170 to 200 nm. An increase in docetaxel release at acidic pH was observed for all micelles. Enhanced cellular internalization of Nile red doped micelles by MDA-MB-231 human breast cancer cells suggested that the most efficient uptake was observed with targeted micelles. In vitro cytotoxicity experiments on MDA-MB-231 breast cancer and A549 lung carcinoma cell lines showed improved toxicity for RGD containing micelles. For A549 cell line EC values of drug loaded micellar sets were in the range of 10 M whereas EC value of free docetaxel was around 10 M. For MDA-MB-231 cell line EC value of free docetaxel was 6 × 10 M similar to EC of nontargeted AB type docetaxel doped micellar constructs whereas the EC value of its targeted counterpart decreased to 5.5 × 10 M. Overall, in this comparative study, the targeting group containing micellar construct fabricated with a 2 kDa PEG based diblock dendron-polymer conjugate emerges as an attractive drug delivery vehicle due to the ease of synthesis, high stability of the micelles, and efficient targeting.

Telodendrimers: Promising Architectural Polymers for Drug Delivery

“…As the general chemical methodologies involved in the synthesis of telodendrimers were becoming available, the biological perspective of their applications became the next focus [ 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 ]. As noted by Newkome in 1985, it was the search for an architectural outline with the ability to form micelles that inspired the scientific community about these hybrid structures.…”

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

“…In a recent study, Sanyal and coworkers reported a modular micellar system for delivery of docetaxel. An AB type diblock dendron polymer conjugate was used to introduce targeting RGD (arginine-glycine-aspartic acid) peptides onto NP surface ( Scheme 10 ) [ 92 ]. The peptide targeting group containing diblock copolymer was composed of a linear PEG polymer appended with an acetal protected hydrophobic polyester dendron at one end and the cyclic RGD peptide targeting unit at the other end.…”

“… Illustration of drug loaded, RGD targeted micellar NPs via “Mix-and-Match” approach employing AB and ABA type dendron−polymer constructs. Reprinted with permission from [ 92 ]. Copyright (2017) American Chemical Society.…”

Dual disassembly and biological evaluation of enzyme/oxidation-responsive polyester-based nanoparticulates for tumor-targeting delivery

“…[14][15][16][17][18] Acidic pH, glutathione, reactive oxygen species (ROS), and enzymatic activities are typical examples of endogenous stimuli, while light and temperature are exogenous stimuli. [19][20][21] The response to these stimuli has led to more precise control over the dissociation or disintegration of smart PDDS. [22][23][24] In particular, enzyme-responsive systems are especially promising in that enzymes are great catalysts with high selectivity towards specific substrates.…”