An amphiphilic graft copolymer-based nanoparticle platform for reduction-responsive anticancer and antimalarial drug delivery

Abstract

Medical applications of anticancer and antimalarial drugs often suffer from low aqueous solubility, high systemic toxicity, and metabolic instability. Smart nanocarrier-based drug delivery systems provide means of solving these problems at once. Herein, we present such a smart nanoparticle platform based on self-assembled, reduction-responsive amphiphilic graft copolymers, which were successfully synthesized through thiol-disulfide exchange reaction between thiolated hydrophilic block and pyridyl disulfide functionalized hydrophobic block. These amphiphilic graft copolymers self-assembled into nanoparticles with mean diameters of about 30-50 nm and readily incorporated hydrophobic guest molecules. Fluorescence correlation spectroscopy (FCS) was used to study nanoparticle stability and triggered release of a model compound in detail. Long-term colloidal stability and model compound retention within the nanoparticles was found when analyzed in cell media at body temperature. In contrast, rapid, complete reduction-triggered disassembly and model compound release was achieved within a physiological reducing environment. The synthesized copolymers revealed no intrinsic cellular toxicity up to 1 mg mL(-1). Drug-loaded reduction-sensitive nanoparticles delivered a hydrophobic model anticancer drug (doxorubicin, DOX) to cancer cells (HeLa cells) and an experimental, metabolically unstable antimalarial drug (the serine hydroxymethyltransferase (SHMT) inhibitor (±)-1) to Plasmodium falciparum-infected red blood cells (iRBCs), with higher efficacy compared to similar, non-sensitive drug-loaded nanoparticles. These responsive copolymer-based nanoparticles represent a promising candidate as smart nanocarrier platform for various drugs to be applied to different diseases, due to the biocompatibility and biodegradability of the hydrophobic block, and the protein-repellent hydrophilic block.

Mimicking Cellular Signaling Pathways within Synthetic Multicompartment Vesicles with Triggered Enzyme Activity and Induced Ion Channel Recruitment

“…We then loaded nanoassemblies into GUVs with the intention of creating a multicompartmentalized architecture ( Figure A). Depending on the chemical nature of the copolymers and their molecular properties, various nanoassemblies were formed: i) reduction‐sensitive nanoparticles (NP‐Graft) based on (poly(2‐methyl‐2‐oxazoline) 88 ‐ graft (SS)‐poly(ε‐caprolactone) 238 (PMOXA 88 ‐ g (SS)‐PCL 238 ), ii) nonsensitive nanoparticles (NP‐Control) based on poly(2‐methyl‐2‐oxazoline) 30 ‐ block ‐poly(ε‐caprolactone) 62 (PMOXA 30 ‐ b ‐PCL 62 ), iii) micelles resulting from PDMS 65 ‐ b ‐heparin (M100), and iv) polymersomes formed from a mixture of PMOXA 5 ‐ b ‐PDMS 58 ‐ b ‐PMOXA 5 combined with 5% or 25% PDMS 65 ‐ b ‐heparin (Ves5 and Ves25, respectively) . We investigated the architecture and size of these nanoassemblies by a combination of transmission electron microscopy (TEM) and dynamic light scattering (DLS).…”

“…As expected, the nanoparticle disassembly was delayed when encapsulated within GUVs due to the additional barrier (GUV membrane). Indeed, in solution, the disassembly of NP‐Graft nanoparticles and their content release was complete within 90 min, whereas it took 24 h to reach 90% for NP‐Graft as subcompartments within GUVs. More specifically, in an average GUV volume of 1112 ± 407 µm 3 , the average nanoparticle number of 4082 ± 1051 initially encapsulated dropped to 80 ± 23 after 48 h in presence of DTT (Figure S7A, Supporting Information).…”

“…TEM micrographs indicated the formation of spherical nanoparticles and DLS revealed hydrodynamic diameters of 52 ± 23 nm (for NP‐Graft), and 104 ± 40 nm (for NP‐Control). The hydrodynamic diameter of micelles M100 was 99 ± 34 nm, while polymersomes had diameters of 142 ± 55 nm (for Ves5) and 159 ± 57 nm (for Ves25), in agreement with our previous reports …”

“…Consistently, the hydrodynamic diameters calculated for the nanoassemblies inside GUVs were comparable to the DLS data obtained from the free nanoassemblies in solution (Figure F). This data is in agreement with the values reported previously . The subcompartments freely diffused within the lumen of the GUVs and did not aggregate inside.…”

“…In particular, stimuli‐responsive single polymer‐based nanocompartments were proposed as drug delivery systems, nanoreactors, artificial organelles/cells, depending on their payload and the properties of their membrane. Stimuli‐responsiveness was achieved either by designing copolymers with a special chemical nature, inducing a change in the membrane permeability or even its disintegration upon a change in their environment. Alternatively, functional insertion of ion channels (biopores) and membrane proteins allowed induction of membrane permeability owing to their intrinsic functionality …”