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

Bioconjug Chem. 2017 Dec 20;28(12):2962-2975. doi: 10.1021/acs.bioconjchem.7b00595. Epub 2017 Dec 6.

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 αυβ3υβ5 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 10-6 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 EC50 values of drug loaded micellar sets were in the range of 10-9 M whereas EC50 value of free docetaxel was around 10-10 M. For MDA-MB-231 cell line EC50 value of free docetaxel was 6 × 10-8 M similar to EC50 of nontargeted AB type docetaxel doped micellar constructs whereas the EC50 value of its targeted counterpart decreased to 5.5 × 10-9 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.

MeSH terms

  • A549 Cells
  • Cell Survival / drug effects
  • Dendrimers / chemistry*
  • Dendrimers / toxicity
  • Drug Design*
  • Drug Liberation
  • Humans
  • Hydrogen-Ion Concentration
  • Micelles
  • Models, Molecular
  • Molecular Conformation
  • Peptides, Cyclic / chemistry
  • Polyethylene Glycols / chemistry

Substances

  • Dendrimers
  • Micelles
  • Peptides, Cyclic
  • cyclic arginine-glycine-aspartic acid peptide
  • Polyethylene Glycols