Joana R. Góis

Drug delivery systems: Advanced technologies potentially applicable in personalized treatments

Advanced drug delivery systems (DDS) present indubitable benefits for drug administration. Over the past three decades, new approaches have been suggested for the development of novel carriers for drug delivery. In this review, we describe general concepts and emerging research in this field based on multidisciplinary approaches aimed at creating personalized treatment for a broad range of highly prevalent diseases (e.g., cancer and diabetes). This review is composed of two parts. The first part provides an overview on currently available drug delivery technologies including a brief history on the development of these systems and some of the research strategies applied. The second part provides information about the most advanced drug delivery devices using stimuli-responsive polymers. Their synthesis using controlled-living radical polymerization strategy is described. In a near future it is predictable the appearance of new effective tailor-made DDS, resulting from knowledge of different interdisciplinary sciences, in a perspective of creating personalized medical solutions.

Improvement of the control over SARA ATRP of 2-(diisopropylamino)ethyl methacrylate by slow and continuous addition of sodium dithionite

The kinetics and detailed mechanism of SARA ATRP of 2-(diisopropylamino)ethyl methacrylate (DPA) were investigated. Supplemental activator and reducing agent (SARA) atom transfer radical polymerization (ATRP) using sodium dithionite (Na2S2O4) was used to create well controlled polymers of PDPA. The influence of the initiator, solvent, structure and concentration of the catalyst was studied, and the ratios of Na2S2O4 were adjusted to optimize the polymerization. Well controlled polymers required Na2S2O4 to be slowly and continuously fed to the reaction mixture, with 500 parts per million (ppm) of CuBr2 with tris(2-dimethyamino)amine (Me6TREN) as a ligand. The initial content of Na2S2O4 in the reaction mixture, the feeding rate and the Cu catalyst concentration were optimized to provide polymers with narrow molecular weight distribution (Mw/Mn < 1.15) at high monomer conversion (∼90%). Interestingly, the results revealed that when tris(2-pyridylmethyl)-amine (TPMA) was used as a ligand, the amount of copper required to achieve similar control of the polymerization could be decreased 5 times. This system was successfully extended to the polymerization of oligo(ethylene oxide) methyl ether methacrylate (OEOMA). The high conversion and preservation of the chain-end functionality allows the direct synthesis of POEOMA-b-PDPA block copolymers. The low catalyst concentrations and benign nature of Na2S2O4 make this SARA ATRP method attractive for the synthesis of well controlled water soluble polymers for biomedical applications.

Synthesis of well-defined functionalized poly(2-(diisopropylamino)ethyl methacrylate) using ATRP with sodium dithionite as a SARA agent

2-(Diisopropylamino)ethyl methacrylate (DPA) was polymerized by Atom Transfer Radical Polymerization (ATRP) using sodium dithionite (Na2S2O4) as a reducing agent and supplemental activator with a Cu(II)Br2/Me6TREN catalytic system at 40 °C in an isopropanol–water mixture. The effects of the solvent mixture and the initiator structure on the polymerization kinetics were studied. The eco-friendly catalytic system described is suitable for the synthesis of poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) with controlled molecular weight, low dispersity, and well-defined chain-end functionality. Both linear and 4-arm star polymers with various target molecular weights were synthesised. The 1H NMR and MALDI-TOF analyses confirmed the molecular structure and high chain-end functionality of the obtained polymers. The use of an alkyne functionalized initiator allowed further azide–alkyne Huisgen cycloaddition with 3-azido-7-diethylamino-coumarin, a fluorescent biocompatible molecule.

Synthesis of functionalized poly(vinyl acetate) mediated by alkyne-terminated RAFT agents

Two new xanthates with alkyne functionalities were synthesized for the reversible addition fragmentation chain transfer (RAFT) polymerization of vinyl acetate (VAc). The new RAFT agents were fully characterized by 1H and 13C NMR spectroscopy. Unlike the alkyne terminated RAFT agent (AT-X1) the protected alkyne-terminated RAFT agent (PAT-X1) was able to conduct the RAFT polymerization of VAc with a good control over the molecular weight (MW) and relatively narrow MW distributions (Đ < 1.4). The linear evolution of Mn with conversion as well as the close agreement between Mn,th and Mn,GPC values confirmed the controlled features of the RAFT system. It is worth mentioning that the polymer dispersity remained very low (Đ < 1.20) until relatively high monomer conversions (60%) due to the non-activated nature of VAc. The chain end-functionality of the obtained polymers was evaluated by 1H NMR, FTIR-ATR and UV-Vis absorption analysis. The “livingness” of the obtained polymer was confirmed by a successful chain extension experiment. The deprotection of the alkyne functionality in the PVAc, allowed a further copper catalyzed azide–alkyne [3 + 2] dipolar cycloaddition reaction (CuAAC) with an azido terminated-poly(ethylene glycol) (PEG-N3), to afford PVAc–PEG block-copolymers as a proof-of-concept.

Release of Volatile Compounds from Polymeric Microcapsules Mediated by Photocatalytic Nanoparticles

In this study we propose a suitable method for the solar-activated controlled release of volatile compounds from polymeric microcapsules bonded with photocatalytic nanoparticles. These reservoirs can find applications, for example, in the controlled release of insecticides, repellents, or fragrances, amongst other substances. The surfaces of the microcapsules have been functionalized with TiO2 nanoparticles. Upon ultraviolet irradiation, redox mechanisms are initiated on the semiconductor surface resulting in the dissociation of the polymer chains of the capsule wall and, finally, volatilization of the encapsulated compounds. The quantification of the output release has been performed by gas chromatography analysis coupled with mass spectroscopy.

The Importance of Controlled/Living Radical Polymerization Techniques in the Design of Tailor Made Nanoparticles for Drug Delivery Systems

Recent developments in controlled/living radical polymerization methods (CLRP) have created the opportunity to prepare polymeric based systems with site specific functionality that has significantly expanded the range of physical and chemical properties that can be generated in materials prepared by these systems. For example, CLRP prepared block copolymers can self-assemble into nanoparticles that can be used in drug delivery applications. The development of synthetic procedures for preparation of materials targeting new and more efficient drug delivery systems (DDS) is of great interest since ultimately they can mimic most of the properties of biological systems.

Synthesis of well-defined alkyne terminated poly(N-vinyl caprolactam) with stringent control over the LCST by RAFT

The reversible addition-fragmentation chain transfer (RAFT) of N-vinyl caprolactam (NVCL) using two new xanthates with alkyne functionalities is reported. The kinetic data obtained for polymerization of this non-activated monomer using a protected alkyne-terminated RAFT agent (PAT-X1) revealed a linear increase of the polymer molecular weight with the monomer conversion as well as low dispersity (Đ) during the entire course of the polymerization. The system reported here allowed us to enhance the final conversion, diminish Đ and reduce the polymerization temperature compared to the typical values reported in the scarce literature available for the RAFT polymerization of NVCL. The resulting PNVCL was fully characterized using 1H nuclear magnetic resonance (1H NMR), matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), Fourier-transform infrared spectroscopy (FTIR) and gel permeation chromatography (GPC) techniques. The temperature-responsive features of PNVCL in aqueous solutions were fully investigated under different conditions using turbidimetry. The presented strategy allows the synthesis of well-defined PNVCL with sharp and reversible phase transition temperatures around 37 °C. By manipulating the polymer molecular weight, or the solution properties, it is possible to tune the PNVCL phase transition. As a proof-of concept, the alkyne functionalized PNVCL was used to afford new linear block copolymers, by reacting with an azide-terminated poly(ethylene glycol) (N3-PEG) through the copper catalyzed azide-alkyne [3+2] dipolar cycloaddition (CuAAC) reaction. The results presented establish a robust system to afford the synthesis of PNCVL with fine tuned characteristics that will enable more efficient exploration of the remarkable potential of this polymer in biomedical applications.

Facile synthesis of well-controlled poly(glycidyl methacrylate) and its block copolymers via SARA ATRP at room temperature

The detailed synthesis of poly(glycidyl methacrylate) (PGMA) by atom transfer radical polymerization (ATRP) using a catalytic system of Fe(0)/Cu(II)Br2 at room temperature is reported. The reaction system was optimized with regard to the ligand structure, solvent mixture and temperature. The kinetic data confirmed the controlled character of ATRP of GMA revealing a linear increase in molecular weight with conversion, very low dispersity (Đ < 1.1) and the complete retention of chain end functionality. The molecular structure of PGMA was confirmed by 1H NMR. As a proof-of-concept, hybrid block copolymers of poly(dimethyl siloxane)-b-PGMA were prepared using ppm concentrations of soluble copper and a mixture of solvents. The results presented in this manuscript demonstrated the robustness of the catalytic system to afford PGMA and its block copolymers with controlled structures that can be further functionalized exploring the portfolio of chemistries involving the oxirane ring.

Room temperature aqueous self-assembly of poly(ethylene glycol)-poly(4-vinyl pyridine) block copolymers: From spherical to worm-like micelles.

The solution self-assembly and the formation, at room temperature, of a wide range of nanostructures based on monomethyl ether poly(ethylene glycol)-b-poly(4-vinyl pyridine) (mPEG-b-P4VP) block copolymer is reported. Copolymers with different compositions and molecular weights were synthesized through Atom Transfer Radical Polymerization (ATRP) method. The solution self-assembly of the block copolymers was studied by transmission electron microscopy (TEM) for different solution pHs. It was found that the formation of non-spherical nanostructures, such as rod- and worm-like micelles can be easily achieved, at room temperature, by simply varying the molecular weight of the different segments as well as the mPEG to P4VP ratio in the block copolymer structure. Because P4VP segments are known to form strong complexes with metals, the nanostructures prepared in this manuscript can find innovative applications in the biomedical field and be used as nano-templates for inorganic materials.

Drug Delivery Systems for Predictive Medicine: Polymers as Tools for Advanced Applications

Predictive medicine represents a new philosophy in healthcare involving the detection of pathology-specific molecular patterns before the emergence of signs and symptoms, which in some diseases (e.g., diabetes) surged accompanied by severe secondary complications. Advanced drug delivery systems (DDS) present important benefits for this new and fascinating area, since they enable to deploy active molecules in specific targeted regions of the body in a controlled manner. The exponential development achieved in DDS during the last decades can be used to develop effective solutions for the premature detection and effective treatment of different pathologies. Polymers provide the ideal opportunities for the development of new effective DDS due to the easy processing and to the control over the physical and chemical characteristics that can be accomplished during the polymerization.