Stimuli Responsive Polymers for Enhanced Drug Release Applications

This talk will focus on the development of polymeric nano-structured systems for drug and gene delivery applications. Two major classes of polymer systems will be considered; namely poly(ethylene-oxide-b-propylene-oxide-b-ethylene-oxide) (Pluronics) tri-block copolymers (FDA approved) and methacrylic acid (MAA) block and random copolymers. These polymers were functionalised with biodegradable or stimuli-sensitive functional groups to produce stimuli-sensitive nano-structure for efficient delivery of drugs and DNAs. The atom transfer radical polymerisation (ATRP) was adopted to synthesize a range of mono-dispersed block copolymers (e.g. PEO-b-MAA, MMA-b-MAA). Ring opening polymerization method was used to functionalize Pulronics with degradable functional groups, such as lactide (LA), and caprolactone (CL). Other stimuli-sensitive functional groups such as methacrylic acid was used to impart pH sensitivity to the polymers. Various types of methacrylic acid block and random cross-linked copolymers and other novel systems, such as fullerene based block copolymers were synthesized. Detailed mechanism and physics that control the micellization, microstructure and drug/polymer interactions will be discussed.Singapore-MIT Alliance (SMA

Association Behavior of Poly(methacrylic acid)-block-Poly(methyl methacrylate) in Aqueous Medium: Potentiometric and Laser Light Scattering Studies

Atom transfer radical polymerisation (ATRP) technique was used to synthesize poly(methacrylic acid-block-methyl methacrylate) (P(MAA₁₀₂-b-MMA₁₀)) copolymer in order to study the aggregation behavior in aqueous solution over the course of neutralization. A combination of static and dynamic light scattering (SLS, DLS) and potentiometric titration techniques were used to investigate the size and shape of the micelle at various degrees of neutralization. The hydrodynamic radius (Rh) determined from dynamic light scattering increases from ~26nm (for unneutralized) to ~42nm (for completely neutralized sample). Both potentiometric and laser light scattering studies indicate the formation of a core shell micelle. The weighted average molecular weights of the polymer and micelle are 1.18x10⁴ and 2.25 x 10⁵ g/mol respectively, which suggests that the aggregation number of the micelle is ~20.Singapore-MIT Alliance (SMA

Novel pH Responsive Amphiphilic Diblock Copolymers with Reversible Micellization Properties

Di-block copolymer of poly[methacrylic acid-block-2-(diethylamino)ethyl methacrylate] [P(MAA-b-DEA)] with narrow molecular weight distribution was synthesized using the atom transfer radical polymerization (ATRP) technique. The micellization behavior of the P(MAA-b-DEA) copolymer in aqueous solution at room temperature and different pH values were examined by potentiometric and conductivity titration, UV-Visible spectrophotometry, ¹H-NMR, static and dynamic laser light scattering. At low pH ( 9.5), core-shell like micelles consisting of hydrophobic DEA core and ionized MAA shell were re-established.Singapore-MIT Alliance (SMA

Association Behavior of Poly (methyl methacrylate-b-methacrylic acid-b-methyl methacrylate) in Aqueous Medium

ABA type tri-block amphiphilic polyelectrolyte consisting of poly(methyl methacrylate-block-methacrylic acid-block-methyl methacrylate) (P(MMA-b-MAA-b-MMA)) was synthesized by atom transfer radical polymerization technique (ATRP) and the self-assembly behavior of the polymers in aqueous solution was studied over the course of neutralization. Combination of potentiometric and conductometric titrations along with dynamic light scattering (DLS) techniques were used to investigate the size and shape of aggregates at various degrees of neutralization. The effect of hydrophobic-hydrophilic (MMA-MAA) ratio and polymer chain length on the aggregation behavior during neutralization was studied. P(MMA-b-MAA-b-MMA) with longer MMA segment self-assembles via the close association mechanism through stronger self-entanglement of MMA chains, whereas P(MMA-b-MAA-b-MMA) with shorter MMA chain self-assembles via the open association mechanism, as confirmed by transmission electron microscopy (TEM). Conductometric titration was used to determine the counterion condensation during the course of neutralization. When the charge density of micelle approaches a critical value as neutralization progresses, counterion condensation of Na+ ions on the polymer chains occurs. The effect of counterion condensation on the aggregation behavior during neutralization was elucidated.Singapore-MIT Alliance (SMA

Titration Microcalorimetry Study: Interaction of Drug and Ionic Microgel System

Doxorubicin (DOX) and Pluronic-PAA interaction was investigated using isothermal titration calorimetry (ITC). DOX/polymer interaction is governed primarily by electrostatic interaction. The uptake of DOX results in the formation of insoluble polymer/DOX complex. Addition of salt weakens the interaction of drug and polymer by charge shielding effect between positive ionized amino group on DOX and oppositely charged polymer chains. However high drug-loading capacity in high salt condition implied that self-association property of DOX also play a role in the drug loading process.Singapore-MIT Alliance (SMA

Particle Migration of Quasi-Steady Flow in Concentrated Suspension for Powder Injection Molding

A hybrid FEM/FDM algorithm for particle migration of quasi-steady flow in concentrated suspension materials is proposed in this study. This hybrid FEM/FDM algorithm in which the planar variables, such as pressure field, are described in terms of finite element method, and gapwise variables of temperature, density concentration and time derivatives are expressed by finite difference method. The particle concentration inhomogeneities can be predicted, which is ignored by the existing injection molding simulation packages. Simulation results indicated that powder concentration variation could be significant in practical processing in PIM.Singapore-MIT Alliance (SMA

Synthesis and Complexation Behavior of Pluronic-b-Poly(acrylic Acid) Copolymer with Doxorubicin

Poly(acrylic acid) (PAA) was attached on both termini of Pluronic P85 copolymer (EO27PO39EO27)) via atom transfer radical polymerization (ATRP) to produce a novel block copolymer, PAA-b-P85-b-PAA (P85PAA). The P85PAA-DOX complex formation and drug loading were strongly dependent on the PAA segment and pH, where the protonation of the carboxyl groups in the PAA segment at pH<7.2 reduced the binding sites of DOX onto P85PAA chains, resulting less DOX uptake at low pH. The composition of the copolymer-DOX complexes that at pH 7.2 was close to the stoichiometric (1:1 mol Dox:carboxyl ratio), indicating the dominance of the electrostatic interactions between cationic DOX molecules and carboxyl groups. DOX loading at pH 5.0 reduced to 0.6:1 molar ratio of DOX:carboxyl indicated that protonation of the carboxyl reduced the DOX binding to the P85PAA block copolymer. DOX release from the complex is highly pH-responsive process, where 57% of encapsulated DOX was released in 30h at pH7.2, and the cumulative release fraction was accelerated to 95% by decreasing the pH to 5.0. Thus, complexation of DOX with P85PAA yielded a drug delivery system affording a pH-triggered release of DOX in acidic environment pH5.0.Singapore-MIT Alliance (SMA

Cellulose nanocrystals in smart and stimuli-responsive materials: a review

“Smart” stimuli-responsive materials have been the subject of decades of research because of their versatility and particularly their use in medical and sensing applications. While these materials are often composed exclusively of responsive polymers, there is growing interest in smart hybrid systems that contain at least two distinct components, each contributing uniquely to the final material. Cellulose nanocrystals (CNCs) have found extensive application in smart hybrid systems, as CNCs can both contribute to the mechanical and optical properties of the system and bear stimuli-responsive surface modifications. This review covers the recent body of work on CNC-containing smart hybrid systems, with attention given to the fabrication methodologies that have been employed to generate both physically and optically adaptable CNC-based smart systems. Additionally, the unique application of CNCs in self-healing composites and shape memory polymers will be discussed.Natural Sciences and Engineering Research Council of Canad

Rheological and Thermodynamic Properties of PEO-PPE-PEO and PAA-g-PEO-PPO-PEO System

Rheological and thermodynamic properties of Pluronic F127 copolymer and Pluronic-g-PAA have been studied as a function of temperature and concentration. A combination of rheometry and DSC was employed to examine the gelation behavior of F127 and F127-g-PAA. The viscosity of F127 is extremely sensitive to temperature when the polymer concentration exceeds 10 wt%. But significant increase of viscosity has been observed for 1.0 wt%F127-PAA aqueous solution as a function of temperature. This could be due to the PAA grafts, acting as cross-links attached to the F127 backbone.Singapore-MIT Alliance (SMA