Temperature-sensitive polymers for drug delivery.

The ability to undergo rapid changes in response to subtle environmental cues make stimuli- responsive materials attractive candidates for minimally invasive, targeted and personalized drug delivery applications. This special report aims to highlight and provide a brief description of several of the significant natural and synthetic temperature-responsive materials that have clinical relevance for drug delivery applications. This report examines the advantages and disadvantages of natural versus synthetic materials and outlines various scaffold architectures that can be utilized with temperature-sensitive drug delivery materials. The authors provide a commentary on the current state of the field and provide their insight into future expectations for temperature-sensitive drug delivery, emphasizing the importance of the emergence of dual and multiresponsive systems capable of responding precisely to an expanding set of stimuli, thereby allowing the development of disease-specific drug delivery vehicles.

Cell-adhesive thermogelling PNIPAAm/hyaluronic acid cell delivery hydrogels for potential application as minimally invasive retinal therapeutics.

Copolymers of N-isopropylacrylamide (NIPAAm) and acrylic acid N-hydroxysuccinimide (NAS) were synthesized via free radical polymerization and conjugated with amine-functionalized hyaluronic acid (HA) and cell adhesive RGDS peptides. These novel copolymers were designed to facilitate noninvasive delivery of a liquid suspension of cells into the delicate subretinal space for treatment of retinal degenerative diseases such as age-related macular degeneration (AMD) and diabetic retinopathy. The various synthesized copolymers all displayed subphysiological phase transition temperatures, thereby allowing temperature-induced scaffold formation and subsequent entrapment of transplanted cells within an adhesive support matrix. Successful grafting of HA and RGDS peptides were confirmed with Fourier Transform Infrared (FTIR) spectroscopy and quantified with (1)H Nuclear Magnetic Resonance (NMR) spectroscopy. All copolymers demonstrated excellent compatibility with retinal pigment epithelial (RPE) cells in culture and minimal host response was observed following subcutaneous implantation into hairless SKH1-E mice (strain code 447).

Development of injectable, resorbable drug-releasing copolymer scaffolds for minimally invasive sustained ophthalmic therapeutics.

Copolymers based on N-isopropylacrylamide (NIPAAm), acrylic acid N-hydroxysuccinimide (NAS) and varying concentrations of acrylic acid (AA) and acryloyloxy dimethyl-γ-butyrolactone (DBA) were synthesized to create thermoresponsive, resorbable copolymers for minimally invasive drug and/or cell delivery to the posterior segment of the eye to combat retinal degenerative diseases. Increasing DBA content was found to decrease both copolymer water content and lower critical solution temperature. The incorporation of NAS provided an amine-reactive site, which can be exploited for facile conjugation of bioactive agents. Proton nuclear magnetic resonance analysis revealed the onset of hydrolysis-dependent opening of the DBA lactone ring, which successfully eradicated copolymer phase transition properties and should allow the gelled polymer to re-hydrate, enter systemic circulation and be cleared from the body without the production of degradation byproducts. Hydrolytic ring opening occurs slowly, with over 85% copolymer mass remaining after 130 days of incubation in 37°C phosphate buffered saline. These slow-degrading copolymers are hypothesized to be ideal delivery vehicles to provide minimally invasive, sustained, localized release of pharmaceuticals within the posterior segment of the eye to combat retinal degenerative diseases.

PNIPAAm-grafted-collagen as an injectable, in situ gelling, bioactive cell delivery scaffold.

We synthesized two thermoresponsive, bioactive cell scaffolds by decorating the backbone of type I bovine collagen with linear chains of poly(N-isopropylacrylamide) (PNIPAAm), with the ultimate aim of providing facile delivery via injection and support of retinal pigment epithelial (RPE) cells into the back of the eye for the treatment of retinal degenerative diseases. Both scaffolds displayed rapid, subphysiological phase transition temperatures and were capable of noninvasively delivering a liquid suspension of cells that gels in situ forming a cell-loaded scaffold, theoretically isolating treatment to the injection site. RPE cells demonstrated excellent viability when cultured with the scaffolds, and expulsion of cells arising from temperature-induced PNIPAAm chain collapse was overcome by incorporating a room-temperature incubation period prior to scaffold phase transition. These results indicate the potential of using PNIPAAm-grafted-collagen as a vehicle for the delivery of therapeutic cells to the subretinal space.

Responding to change: thermo- and photo-responsive polymers as unique biomaterials.

Responsive polymer systems that react to thermal and light stimuli have been a focus in the biomaterials literature because they have the potential to be less invasive than currently available materials and may perform well in the in vivo environment. Natural and synthetic polymer systems created to exhibit a temperature-sensitive phase transition lead to in situ forming hydrogels that can be degradable or non-degradable. These systems typically yield physical gels whose properties can be manipulated to accommodate specific applications while requiring no additional solvents or cross-linkers. Photo-responsive isomerization, dimerization, degradation, and triggered processes that are reversible and irreversible may be used to create unique gel, micelle, liposome, and surface-modified polymer systems. Unique wavelengths induce photo-chemical reactions of polymer-bound chromophores to alter the bulk properties of polymer systems. The properties of both thermo- and photo-responsive polymer systems may be taken advantage of to control drug delivery, protein binding, and tissue scaffold architectures. Systems that respond to both thermo- and photo-stimuli will also be discussed because their multi-responsive properties hold the potential to create unique biomaterials.