Microfluidic Synthesis of Block Copolymer Micelles: Application as Drug Nanocarriers and as Photothermal Transductors When Loading Pd Nanosheets

Abstract

The synthesis of polymeric nanoparticles from a block copolymer based on poly(ethylene glycol) and a polymethacrylate containing the nucleobase analog 2,6‐diacylaminopyridine is optimized by microfluidics to obtain homogeneous spherical micelles. Loading and delivery properties are studied using naproxen as a model. The incorporation of a Pd precursor in the polymer organic solution fed into the micromixer allows the preparation of Pd(II) precursor‐polymer hybrid systems and the subsequent reduction with CO leads to the in situ synthesis of Pd nanosheets inside of the hydrophobic core of the polymeric micelles. This methodology is highly efficient to yield all polymeric nanoparticles loaded with Pd nanosheets as detected by electron microscopy and energy‐dispersive X‐ray spectroscopy. The cell viability of these Pd nanosheets‐containing polymeric nanoparticles is evaluated using five cell lines, showing a high cytocompatibility at the tested concentrations without detrimental effects in cell membrane and nuclei. Furthermore, the use of these hybrid polymeric nanoparticles as photothermal transductors is evaluated using near infrared as irradiation source as well as its application in photothermal therapy using different cell lines demonstrating a high efficiency in all cell cultures.

Aqueous seeded RAFT polymerization for the preparation of self-assemblies containing nucleobase analogues

“…15 PISA polymerization of HMPA has been approached using several macro-CTAs or hydrophilic stabilizer blocks such as poly(glycerol methacrylate), 15,23,[27][28][29]43,44 poly(2-(methacryloyloxy)ethyl phosphorylcholine) 26 or poly(ethylene glycol) (PEG) 13,17,30,33,43,[45][46][47][48] or even statistical copolymers like poly (glycerol methacrylate-st-glycidyl methacrylate). 31,36 For some time now, our group has worked on the synthesis and self-assembly of linear-linear 7,49,50 and linear-dendritic 51 amphiphilic BCs containing a PEG hydrophilic block and a hydrophobic one bearing the 2,6-diacylaminopyridine (DAP) unit, which is a nucleobase analogue able to form multiple hydrogen bonds, for different purposes. Furthermore, PEG has been recurrently employed in biomedical applications given that it is non-toxic and able to reduce immunogenicity, which enables the extension of in vivo circulation lifetimes of any encapsulated molecules.…”

“…Furthermore, PEG has been recurrently employed in biomedical applications given that it is non-toxic and able to reduce immunogenicity, which enables the extension of in vivo circulation lifetimes of any encapsulated molecules. 52 These DAP-containing amphiphilic BCs exhibited excellent self-assembly behavior forming homogeneous dispersions of micelles or vesicles either by solventswitching or microfluidics, and their potential as nanocarriers has been evaluated using fluorescent probes, 7,[49][50][51] or camptothecin 49 and naproxen 7 as drug models. The cell viability of these systems was confirmed on several cell lines as well as the pH 49 and light-stimulated 50 release of the cargoes, in the last case using thymine-containing azocompounds as photoresponsive moieties supramolecularly linked to DAP units.…”

“…Recently, this outstanding self-assembly behavior has been exploited to process hybrid systems consisting of plasmonic Pd(0) nanosheets, grown inside of polymeric micelles, for photothermal therapy under NIR stimulation. 7 In order to further exploit the potential of incorporating nucleobase analogues such as DAP units into amphiphilic BCs, this work explores the preparation of highly concentrated aqueous self-assembly dispersions using the PISA methodology and the supramolecular H-bonding functionalization of the formed self-assemblies. Although there are some examples on the dispersion RAFT polymerization of nucleobases, such as the polymerization of adenine-and thymine-containing monomers in chloroform or dioxane by Kang et al, 14,16 to the best of our knowledge neither nucleobase nor nucleobase analogues have been employed in RAFT-PISA in water.…”

“…1,2 The morphology and size of amphiphilic BC self-assemblies are frequently tailored by adjusting the length of each block, their chemical structure and the processing methodology. 1 The majority of these self-assembly methodologies, such as thin-film rehydration, 3 solvent displacement, 4,5 sonication 6 or microfluidics, 7 are post-polymerization processes which in some cases consist of time-consuming multiple steps and usually provide highly diluted BC dispersions (below 1 wt%). Over the past years, polymerization-induced self-assembly (PISA) has emerged as an attractive one-step alternative where self-assembly occurs during the polymerization, thus avoiding multiple processing or purification steps and also providing highly concentrated self-assembly dispersions (up to 50 wt%) with good colloidal stability.…”

“…For some time now, our group has worked on the synthesis and self-assembly of linear-linear 7,49,50 and linear-dendritic 51 amphiphilic BCs containing a PEG hydrophilic block and a hydrophobic one bearing the 2,6-diacylaminopyridine (DAP) unit, which is a nucleobase analogue able to form multiple hydrogen bonds, for different purposes. Furthermore, PEG has been recurrently employed in biomedical applications given that it is non-toxic and able to reduce immunogenicity, which enables the extension of in vivo circulation lifetimes of any encapsulated molecules.…”