Amphiphilic nanogels based on aliphatic polycarbonates: New biodegradable nanocarriers for hydrophobic compounds

• Applicant: Professor Dr. Daniel Klinger
• Subject Area: Polymer Materials ; Preparatory and Physical Chemistry of Polymers
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 430915250

• Final Report Year: 2023

Final Report Abstract

Overcoming the incompatibility of hydrophobic drugs in pharmaceutical applications is a huge challenge. While stimuli-responsive nanogels are promising drug delivery systems (DDS), they are limited to hydrophilic cargoes. Thus, amphiphilic nanogels (ANGs) are emerging as alternatives that combine multiple features: First, hydrophilic network segments ensure aqueous swelling and flexibility. Second, hydrophobic groups in the network form internal domains to host hydrophobic drugs. Third, cleavable crosslinkers enable stimuli-responsive ANG degradation to induce drug release. Finally, degradable network polymers allow disintegration of ANGs to ensure clearance from the body. To accurately access the therapeutic potential of such multifunctional DDS, this project identified specific criteria to optimize the amphiphilic structure towards loading and release of hydrophobic drugs. Here, a key requirement is to ensure comparability between ANGs of different network composition. For this, we have developed a new synthetic strategy that uses reactive precursor particles for functionalization of the internal network with hydrophilic and hydrophobic moieties after particle preparation. As a result, one batch of precursor particles gives access to ANG libraries with varying network amphiphilicity but comparable colloidal features. In this platform, we have developed tailormade block copolymer surfactants for additional functionalization of the ANG surface - orthogonal to the modification of the internal network. In addition, we have used cleavable crosslinkers to introduce network degradability, e.g., disulfide-based crosslinkers for degradation in a reductive environment. These libraries were used to test the influence of network hydrophobicity on the loading of hydrophobic compounds. Using nile red (NR) as solvatochromic probe, spectroscopic studies revealed a decreasing polarity of NR microenvironment with increasing hydrophobicity of the nanogel network. Increasing NR concentrations resulted in a translocation of NR to more hydrophilic environments and favored dye-dye interactions. These results correlate well with release experiments, that indicate NR is released first from more hydrophilic nanogel domains. While these findings demonstrate the importance of carrier-drug interactions to optimize loading and release, prediction of such interactions is challenging. Thus, we calculated theoretical Flory-Huggins parameters between drug and the amphiphilic network. Correlating these parameters with experimental loading capacities of 15 drugs and dyes gave calibration curves for the prediction of loading contents. Having developed a profound understanding of ANG-cargo interactions, we have transferred our synthetic approach to aliphatic polycarbonates as degradable network polymers. In summary, this project has expanded the potential of ANGs as new DDS by accurately determingin crucial structure-property relations.

Publications

• Struc2drug lecture series Charité Berlin September 2020 Functional Polymer Colloids and Nanomaterials: From Drug Delivery to Dynamic Shape Change
  D. Klinger
  
• Research Colloquium Biophotonics Group BAM Berlin March 2021 Functional Polymer Nanoparticles: From Drug Delivery to Dynamic Shape
  D. Klinger
  
• 51st Biennial Assembly of German Colloid Society Berlin 28-30 of September 2022 A versatile synthetic platform for amphiphilic nanogels: tailoring network hydrophobicity to drug delivery applications
  A. Markovina; C. López Iglesias; A. Gruber & D. Klinger
  
• ACS National Meeting Fall 2022 August 2022 New synthetic strategies to control colloidal properties after particle preparation
  D. Klinger
  
• Dual-reactive nanogels for orthogonal functionalization of hydrophilic shell and amphiphilic network. Soft Matter, 18(14), 2858-2871.
  Gruber, Alexandra; Navarro, Lucila & Klinger, Daniel
  
• Research Colloquium Helmholtz-Zentrum Hereon Teltow June 2022 Controlling Colloidal Properties through Shape, Morphology, and Chemistry
  D. Klinger
  
• Tag der Pharmazie 2022 “Der wissenschaftliche Nachwuchs stellt sich vor – Young scientists present“, FU-Berlin Synthesis, characterization and applications of amphiphilic nanogels based on polymethacrylates, polyesters and polycarbonates
  C. López-Iglesias; R. Cui; A. Markovina; A. Gruber & D. Klinger
  
• 18th Zsigmondy Colloquium 2023 of the German Colloid Society. Berlin, April 4-6, 2023 Encapsulating hydrophobic cargoes in amphiphilic nanogels: Systematic studies on Nile red microenvironment via fluorescence spectroscopy
  A. Markovina; C. López Iglesias; N. Nirmalananthan-Budau; U. Resch-Genger & D. Klinger
  
• Research Colloquium University of Twente (Enschede, Netherlands) October 2023 Adaptive Polymer Nanoparticles for Drug Delivery
  D. Klinger