Microfluidic Assembly To Synthesize Dual Enzyme/Oxidation-Responsive Polyester-Based Nanoparticulates with Controlled Sizes for Drug Delivery

Abstract

Controlling the size and narrow size distribution of polymer-based nanocarriers for targeted drug delivery is an important parameter that significantly influences their colloidal stability, biodistribution, and targeting ability. Herein, we report a high-throughput microfluidic process to fabricate colloidally stable aqueous nanoparticulate colloids with tunable sizes at 50-150 nm and narrow size distribution. The nanoparticulates are designed with different molecular weight polyesters having both ester bonds (responsive to esterase) and sulfide linkages (to oxidative reaction) on the backbones, thus exhibiting dual esterase/oxidation responses, causing the destabilization of the nanoparticulates to lead to the controlled release of encapsulated therapeutics. The systematic investigation on both microfluidic and formulation parameters enables to control their properties as allowing for decreasing nanoparticulate sizes as well as improving colloidal stability and cytotoxicity. Further to such control over smaller size and narrow size distribution, dual stimuli-responsive degradation and excellent cellular uptake could suggest that the microfluidic nanoparticulates stabilized with polymeric stabilizers could offer the versatility toward dual smart drug delivery exhibiting enhanced release kinetics.

Droplet Microfluidics for Tumor Drug‐Related Studies and Programmable Artificial Cells

“…[ 85 ] Such materials actuate a shape deformation that triggers a burst, or sustained release of encapsulants, responding to environmental variations and/or external stimuli. [ 86 ] Stimuli‐responsive microparticles can be fabricated for the selective release of drugs, triggered by electrical fields, [ 87 ] magnetic fields (Figure 3a ), [ 88 ] heating, [ 89 ] ultrasound, [ 90 ] infrared red light, [ 91 ] pH change, [ 92 ] redox, [ 93 ] or the presence of enzymes. [ 94 ] Microparticles can also be engineered to have multifunctionalities, such as sensing, directionality and mobility, which enables the delivery of encapsulants to the target area.…”

“…[ 71 , 75 , 102 ] Biopolymers, such as proteins, gelatin, chitosan and alginate, are used to produce drug‐loaded microparticles using microfluidics to study cell responses, both in vitro and in vivo. [ 103 , 104 , 105 , 106 ] Other stimuli‐responsive microparticles produced using microfluidics include PEG, [ 107 ] polylactide, [ 108 ] graphene oxide, [ 109 ] polyurea, [ 110 ] polyester, [ 93 ] poly(N‐vinylcaprolactam), [ 89 ] and fatty alcohol ( Figure 3 b ), [ 91 ] tailored with properties for various biomedical and drug delivery applications.…”

Synthetic Approaches to Combine the Versatility of the Thiol Chemistry with the Degradability of Aliphatic Polyesters

“…The thiol-ene click reaction represents an efficient and easy step-growth polymerization method which does not lead to the formation of side products, and it has, for example, been exploited to yield polyester chains or networks containing both ester and thioether bonds by reaction between di-thiol-bearing compounds and di-or multi-functional acrylates. [70][71][72] Both thiol-yne and thiol-ene reaction strategies have been exploited for the preparation of bio-based hydroxyl fatty acid that could later undergo condensation polymerization. [73] Figure 16.…”

Novozym 435-Catalyzed Synthesis of Well-Defined Hyperbranched Aliphatic Poly(β-thioether ester)

“…Poly(β-thioether ester)s (PTEs)-one of the sulfur-containing functional polyesters-have gradually attracted attention for drug delivery systems because of their unique acid-degradable and oxidation-responsive properties [24][25][26]. The β-thiopropionate groups in the polymer backbone can be selectively hydrolyzed under mild acidic conditions (pH ~5.5) at a very slow rate [24,27], and the hydrophobic thioethers are known to readily oxidize to more hydrophilic sulfoxides or sulfones when exposed to reactive oxygen species (ROS), such as hypochlorous acid (HClO) or hydrogen peroxides (H 2 O 2 ) [28,29].…”