Nanogels: An overview of properties, biomedical applications and obstacles to clinical translation.
ABSTRACT: Nanogels have emerged as a versatile hydrophilic platform for encapsulation of guest molecules with a capability to respond to external stimuli that can be used for a multitude of applications. These are soft materials capable of holding small molecular therapeutics, biomacromolecules, and inorganic nanoparticles within their crosslinked networks, which allows them to find applications for therapy as well as imaging of a variety of disease conditions. Their stimuli-responsive behavior can be easily controlled by selection of constituent polymer and crosslinker components to achieve a desired response at the site of action, which imparts nanogels the ability to participate actively in the intended function of the carrier system rather than being passive carriers of their cargo. These properties not only enhance the functionality of the carrier system but also help in overcoming many of the challenges associated with the delivery of cargo molecules, and this review aims to highlight the distinct and unique capabilities of nanogels as carrier systems for the delivery of an array of cargo molecules over other nanomaterials. Despite their obvious usefulness, nanogels are still not a commonplace occurrence in clinical practice. We have also made an attempt to highlight some of the major challenges that need to be overcome to advance nanogels further in the field of biomedical applications.
Project description:We report the design, synthesis and efficacy of a new class of gel-like nano-carrier, or 'nanogel', prepared via templated electrostatic assembly of anionic hyaluronic acid (HA) polysaccharides with the cationic peptide amphiphile poly-L-lysine (PLL). Small molecules and proteins present during nanogel assembly become directly encapsulated within the carrier and are precisely released by tuning the nanogel HA:PLL ratio to control particle swelling. Remarkably, nanogels exhibit versatile and complimentary mechanisms of cargo delivery depending on the biologic context. For example, in mammalian cells, nanogels are rapidly internalized and escape the endosome to both deliver membrane-impermeable protein cargo into the cytoplasm and improve chemotherapeutic potency in drug resistant cancer cells. In bacteria, nanogels permeabilize microbial membranes to sensitize bacterial pathogens to the action of a loaded antibiotic. Thus, peptide nanogels represent a versatile, readily scalable and bio-responsive carrier capable of augmenting and enhancing the utility of a broad range of biomolecular cargoes.
Project description:Soft micro- and nanostructures have been extensively developed for biomedical applications. The main focus has been on multifunctional composite materials that combine the advantages of hydrogels and colloidal particles. Magnetic microgels and nanogels can be realized by hybridizing stimuli-sensitive gels and magnetic nanoparticles. They are of particular interest since they can be controlled in a wide range of biological environments by using magnetic fields. In this review, we elucidate physical principles underlying the design of magnetic microgels and nanogels for biomedical applications. Particularly, this article provides a comprehensive and conceptual overview on the correlative structural design and physical functionality of the magnetic gel systems under the concept of colloidal biodevices. To this end, we begin with an overview of physicochemical mechanisms related to stimuli-responsive hydrogels and transport phenomena and summarize the magnetic properties of inorganic nanoparticles. On the basis of the engineering principles, we categorize and summarize recent advances in magnetic hybrid microgels and nanogels, with emphasis on the biomedical applications of these materials. Potential applications of these hybrid microgels and nanogels in anticancer treatment, protein therapeutics, gene therapy, bioseparation, biocatalysis, and regenerative medicine are highlighted. Finally, current challenges and future opportunities in the design of smart colloidal biodevices are discussed.
Project description:Microscale hydrogels consisting of macromolecular networks in aqueous continuous phases have received increasing attention because of their potential use in tissue engineering, cell encapsulation and for the storage and release of cargo molecules. However, for applications targeting intracellular delivery, their micrometer-scale size is unsuitable for effective cellular uptake. Nanoscale analogs of such materials are thus required for this key area. Here, we describe a microfluidics/nanofluidics-based strategy for generating monodisperse nanosized water-in-oil emulsions with controllable sizes ranging from 2500 ± 110 nm down to 51 ± 6 nm. We demonstrate that these nanoemulsions can act as templates to form protein nanogels stabilized by supramolecular fibrils from three different proteins. We further show that these nanoparticles have the ability to penetrate mammalian cell membranes and deliver intracellular cargo. Due to their biocompatibility and lack of toxicity, natural protein-based nanoparticles present advantageous characteristics as vehicles for cargo molecules in the context of pharmaceutical and biomedical applications.
Project description:Safe delivery systems that can not only encapsulate hydrophobic drug molecules, but also release them in response to specific triggers are important in several therapeutic and biomedical applications. In this paper, we have designed a nanogel based on molecules that are generally recognized as safe (GRAS). We have shown that the resultant polymeric nanogels exhibit responsive molecular release and also show high in vitro cellular viability on HEK 293T, HeLa, MCF 7, and A549 cell lines. The toxicity of these nanogels was further evaluated with a highly sensitive assay using mouse preimplantation embryo development, where blastocysts were formed after 4 days of in vitro culture, and live pups were born when morulae/early blastocysts were transferred to the uteri of surrogate recipients. Our results indicate that these nanogels are nontoxic during mammalian development and do not alter normal growth or early embryo success rate.
Project description:In the last years, nanogels have emerged as one of the most promising classes of novel drug delivery vehicles since they can be employed in multiple fields, such as various therapeutics or diagnostics, and with different classes of compounds and active molecules. Their features, such as a high volume to surface ratio, excellent drug loading and release ability, as well as biocompatibility and tunable behavior, are unique, and, nowadays, great efforts are made to develop new formulations that can be employed in a wider range of applications. Polyethylene glycol (PEG)-polyethylenimine (PEI) nanogels probably represent the baseline of this class of biomaterials and they are still largely employed and studied. In any way, the possibility to exploit new core formulations for nanogels is certainly very interesting in order to understand the influence of different polymer chains on the final properties of the system. In this research, we explore and make a comparison between PEG-PEI nanogels and two other different formulations: pluronic F127-PEI nanogels and PEG-Jeffamine nanogels. We propose nanogels synthesis methods, their chemical and physical characterization, as well as their stability analysis, and we focus on the different drug delivery ability that these structures exhibit working with different typologies of drug mimetics.
Project description:Recombinant silk-elastinlike protein polymers (SELPs) combine the biocompatibility and thermoresponsiveness of human tropoelastin with the strength of silk. Direct control over structure of these monodisperse polymers allows for precise correlation of structure with function. This work describes the fabrication of the first SELP nanogels and evaluation of their physicochemical properties and thermoresponsiveness. Self-assembly of dilute concentrations of SELPs results in nanogels with enhanced stability over micelles due to physically crosslinked beta-sheet silk segments. The nanogels respond to thermal stimuli via size changes and aggregation. Modifying the ratio and sequence of silk to elastin in the polymer backbone results in alterations in critical gel formation concentration, stability, aggregation, size contraction temperature, and thermal reversibility. The nanogels sequester hydrophobic compounds and show promise in delivery of bioactive agents.
Project description:Smart gating membranes, inspired by the gating function of ion channels across cell membranes, are artificial membranes composed of non-responsive porous membrane substrates and responsive gates in the membrane pores that are able to dramatically regulate the trans-membrane transport of substances in response to environmental stimuli. Easy fabrication, high flux, significant response and strong mechanical strength are critical for the versatility of such smart gating membranes. Here we show a novel and simple strategy for one-step fabrication of smart gating membranes with three-dimensionally interconnected networks of functional gates, by self-assembling responsive nanogels on membrane pore surfaces in situ during a vapor-induced phase separation process for membrane formation. The smart gating membranes with in situ self-assembled responsive nanogels as functional gates show large flux, significant response and excellent mechanical property simultaneously. Because of the easy fabrication method as well as the concurrent enhancement of flux, response and mechanical property, the proposed smart gating membranes will expand the scope of membrane applications, and provide ever better performances in their applications.
Project description:A novel photo-crosslinkable nanogel is prepared from a biodegradable polymer template with intrinsic photoluminescence and high photostability. The fluorescent nanogels display excellent biodegradability and cytocompatibility owed to the facile synthesis scheme involving a solvent-and surfactant-free one-pot reaction, derived entirely from biocompatible monomers citric acid, maleic acid, L-cysteine, and poly(ethylene glycol). The resultant nanogels are less than 200 nm in diameter with a narrow size distribution and monodispersity, and demonstrate long-term structural stability in biological buffer for two weeks. To gauge potential in theranostic applications, the fluorescent nanogels were surface functionalized with biologically active RGD peptides and encapsulated with active anti-cancer drug Doxorubicin, resulting in a pH-responsive controlled drug release in acidic pH resembling tumor environments. The strong fluorescence of the nanogels enabled tracking of targeted drug delivery, showing that drug-loaded nanogels homed into the cytoplasmic regions of prostate cancer cells to significantly induce cell death. These photo-crosslinkable and biodegradable nanogels pose as a strong candidate for theranostic medicine, demonstrating versatile functionalization, high stability in biological buffers, and capacity for real-time fluorescence-based monitoring of targeted drug delivery.
Project description:Nanogels have been widely used in biomedical applications, such as carriers for hyperthermia cancer treatment, drug delivery, and imaging. Owing to the enhanced permeability and retention effect, nanogels have shown a great potential in cancer therapy. In this study, sodium copper chlorophyllin (SCC), a low cytotoxicity and biodegradable photothermal agent, was copolymerized with a nanogel of N-[3-(dimethylamino)propyl]methacrylamide. The nanogels could produce heat under exposure to a green laser with a 532 nm wavelength. The positively charged nature of the nanogels enhanced the endocytosis of the nanogels. The cell mortality was greatly enhanced with the treatment of the SCC-containing nanogels and green light illumination. Our results suggest the potential of SCC-containing nanogels in photothermal cancer therapy.
Project description:Polyelectrolyte gels are known to undergo significant conformational changes in response to external stimuli such as pH, temperature, or the dielectric constant. Specifically, an increase of the degree of ionization associated with an increasing number of counterions leads to swelling of the network. For a macroscopically large gel, which is electrostatically neutral in its interior, swelling is no longer governed by electrostatic interactions, but rather by the osmotic pressure of counterions. However, this electrostatic neutrality is typically violated for nanogels, because counterions are free to leave a gel particle. Although nanogel-swelling exhibits similar features as swelling of micro- and macrogels, another mechanism has to be relevant. Here, we use molecular dynamics simulations and scaling theory to unravel the structural properties of nanogels upon changing the electrostatic interactions. We demonstrate that the swelling of nanogels is governed by screened electrostatic interactions without a relevant contribution by the counterion osmotic pressure.