Polymeric Nanoparticles Amenable to Simultaneous Installation of Exterior Targeting and Interior Therapeutic Proteins

Effective delivery of therapeutic proteins is a formidable challenge. Herein, using a unique polymer family with a wide‐ranging set of cationic and hydrophobic features, we developed a novel nanoparticle (NP) platform capable of installing protein ligands on the particle surface and simultaneously carrying therapeutic proteins inside by a self‐assembly procedure. The loaded therapeutic proteins (e.g., insulin) within the NPs exhibited sustained and tunable release, while the surface‐coated protein ligands (e.g., transferrin) were demonstrated to alter the NP cellular behaviors. In vivo results revealed that the transferrin‐coated NPs can effectively be transported across the intestinal epithelium for oral insulin delivery, leading to a notable hypoglycemic response.     

Conjugated Polymer Nanoparticles with Appended Photo‐Responsive Units for Controlled Drug Delivery,Release, and Imaging

Carriers that can afford tunable physical and structural changes are envisioned to address critical issues in controlled drug delivery applications. Herein, photo‐responsive conjugated polymer nanoparticles (CPNs) functionalized with donor–acceptor Stenhouse adduct (DASA) and folic acid units for controlled drug delivery and imaging are reported. Upon visible‐light (λ=550 nm) irradiation, CPNs simultaneously undergo structure, color, and polarity changes that release encapsulated drugs into the cells. The backbone of CPNs favors FRET to DASA units boosting their fluorescence. Notably, drug‐loaded CPNs exhibit excellent biocompatibility in the dark, indicating perfect control of the light trigger over drug release. Delivery of both hydrophilic and hydrophobic drugs with good loading efficiency was demonstrated. This strategy enables remotely controlled drug delivery with visible‐light irradiation, which sets an example for designing delivery vehicles for non‐invasive therapeutics.     

Encapsulation and Release Mechanisms in Coordination Polymer Nanoparticles

The interplay of guest encapsulation and release mechanisms in nanoscale metal–organic vehicles and its effect on the drug‐delivery kinetics of these materials were investigated through a new multidisciplinary approach. Two rationally‐designed molecular guests were synthesized, which consist of a red‐fluorescent benzophenoxazine dye covalently tethered to a coordinating catechol group and a protected, non‐coordinating catechol moiety. This allowed loading of the guests into compositionally and structurally equivalent coordination polymer particles through distinct encapsulation mechanisms: coordination and mechanical entrapment. The two types of particles delivered their fluorescent cargo with remarkably different kinetic profiles, which could be satisfactorily modeled considering degradation‐ and diffusion‐controlled release processes. This demonstrates that careful selection of the method of guest incorporation into coordination polymer nanoparticles allows selective tuning of the rate of drug delivery from these materials and, therefore, of the time window of action of the encapsulated therapeutic agents.     

Carboxyl Group (CO2H) Functionalized Coordination Polymer Nanoparticles as Efficient Platforms for Drug Delivery

Functionalization of nanoparticles can significantly influence their properties and potential applications. Although researchers can now functionalize metal, metal oxide, and organic polymer nanoparticles with a high degree of precision, controlled surface functionalization of nanoscale coordination polymer particles (CPPs) has remained a significant challenge. The lack of methodology is perhaps one of the greatest roadblocks to the advancement of CPPs into high added‐value drug delivery applications. Here, we report having achieved this goal through a stepwise formation and functionalization protocol. We fabricated robust nanoparticles with enhanced thermal and colloidal stabilities by incorporation of carboxyl groups and these surface carboxyl groups could be subsequently functionalized through well‐known peptide coupling reactions. The set of chemistries that we employed as proof‐of‐concept enabled a plethora of new functional improvements for the application of CPPs as drug delivery carriers, including enhanced colloidal stabilities and the incorporation of additional functional groups such as polyethylene glycol (PEG) or fluorescent dyes that enabled tracking of their cellular uptake. Finally, we ascertained the cytotoxicity of the new CPP nanoparticles loaded with camptothecin to human breast adenocarcinoma (MCF‐7). Efflux measurements show that the encapsulation of camptothecin enhances the potency of the drug 6.5‐fold and increases the drug retention within the cell.     

J-Aggregate-Based FRET Monitoring of Drug Release from Polymer Nanoparticles with High Drug Loading

Understanding drug-release kinetics is critical for the development of drug-loaded nanoparticles. We developed a J-aggregate-based Förster-resonance energy-transfer (FRET) method to investigate the release of novel high-drug-loading (50 wt %) nanoparticles in comparison with low-drug-loading (0.5 wt %) nanoparticles. Single-dye-loaded nanoparticles form J-aggregates because of the high dye-loading (50 wt %), resulting in a large red-shift (≈110 nm) in the fluorescence spectrum. Dual-dye-loaded nanoparticles with high dye-loading using FRET pairs exhibited not only FRET but also a J-aggregate red-shift (116 nm). Using this J-aggregate-based FRET method, dye-core–polymer-shell nanoparticles showed two release processes intracellularly: the dissolution of the dye aggregates into dye molecules and the release of the dye molecules from the polymer shell. Also, the high-dye-loading nanoparticles (50 wt %) exhibited a slow release kinetics in serum and relatively quick release in cells, demonstrating their great potential in drug delivery.     

Polymer Nanoparticles for Controlled Release Stimulated by Visible Light and pH

Polymer nanoparticles are prepared by self‐assembly of visible light and pH sensitive perylene‐functionalized copolymers which are synthesized by quaternization between 1‐(bromomethyl)perylene and the dimethylaminoethyl units of poly(dimethylaminoethyl methacrylate) (PDMAEMA). The perylene‐containing polymethacrylate segments afford the system visible light responsiveness and the unquaternized PDMAEMA segments afford the system pH responsiveness. The self‐assembled nanoparticles exhibit a unique dual stimuli response. They can be photocleaved under visible light irradiation, shrunken to smaller nanoparticles at high pH, and swollen at low pH. The structural change endows the nanoparticle with great potential as a sensitive nanocarrier for controlled release of Nile Red and lysozyme under this stimulation. The visible light responsiveness and synergistic effect on the release of loaded molecules with the dual stimulation may obviate the need for harsh conditions such as UV light or extreme pH stimulation, rendering the system more applicable under mild conditions.

     

Controlled Multi‐functionalization Facilitates Targeted Delivery of Nanoparticles to Cancer Cells

A major objective of nanomedicine is to combine in a controlled manner multiple functional entities into a single nanoscale device to target particles with great spatial precision, thereby increasing the selectivity and potency of therapeutic drugs. A multifunctional nanoparticle is described for controlled conjugation of a cytotoxic drug, a cancer cell targeting ligand, and an imaging moiety. The approach is based on the chemical synthesis of polyethylene glycol that at one end is modified by a thioctic acid for controlled attachment to a gold core. The other end of the PEG polymers is modified by a hydrazine, amine, or dibenzocyclooctynol moiety for conjugation with functional entities having a ketone, activated ester, or azide moiety, respectively. The conjugation approach allowed the controlled attachment of doxorubicin through an acid‐labile hydrazone linkage, an Alexa Fluor dye through an amide bond, and a glycan‐based ligand for the cell surface receptor CD22 of B‐cells using strain promoted azide‐alkyne cycloaddition. The incorporation of the ligand for CD22 led to rapid entry of the nanoparticle by receptor‐mediated endocytosis. Covalent attachment of doxorubicin via hydrazone linkage caused pH‐responsive intracellular release of doxorubicin and significantly enhanced the cytotoxicity of nanoparticles. A remarkable 60‐fold enhancement in cytotoxicity of CD22 (+) lymphoma cells was observed compared to non‐ targeted nanoparticles.     

Periodic Mesoporous Organosilica Nanoparticles with Controlled Morphologies and High Drug/Dye Loadings for Multicargo Delivery in Cancer Cells

Despite the worldwide interest generated by periodic mesoporous organosilica (PMO) bulk materials, the design of PMO nanomaterials with controlled morphology remains largely unexplored and their properties unknown. In this work, we describe the first study of PMO nanoparticles (NPs) based on meta‐phenylene bridges, and we conducted a comparative structure–property relationship investigation with para‐phenylene‐bridged PMO NPs. Our findings indicate that the change of the isomer drastically affects the structure, morphology, size, porosity and thermal stability of PMO materials. We observed a much higher porosity and thermal stability of the para‐based PMO which was likely due to a higher molecular periodicity. Additionally, the para isomer could generate multipodal NPs at very low stirring speed and upon this discovery we designed a phenylene–ethylene bridged PMO with a controlled Janus morphology. Unprecedentedly high payloads could be obtained from 40 to 110 wt % regardless of the organic bridge of PMOs. Finally, we demonstrate for the first time the co‐delivery of two cargos by PMO NPs. Importantly, the cargo stability in PMOs did not require the capping of the pores, unlike pure silica, and the delivery could be autonomously triggered in cancer cells by acidic pH with nearly 70 % cell killing.     

Thermoresponsive Copolymer/SiO2 Nanoparticles with Dual Functions of Thermally Controlled Drug Release and Simultaneous Carrier Decomposition

The preparation of thermoresponsive drug carriers with a self‐destruction property is presented. These drug carriers were fabricated by incorporation of drug molecules and thermoresponsive copolymer, poly(N‐isopropylacrylamide‐co‐acrylamide), into silica nanoparticles in a one‐pot preparation process. The enhanced drug release was primarily attributed to faster molecule diffusion resulting from the particle decomposition triggered by phase transformation of the copolymer upon the temperature change. The decomposition of the drug carriers into small fragments should benefit their fast excretion from the body. In addition, the resulting drug‐loaded nanoparticles showed faster drug release in an acidic environment (pH 5) than in a neutral one. The controlled drug release of methylene blue and doxorubicin hydrochloride and the self‐decomposition of the drug carriers were successfully characterized by using TEM, UV/Vis spectroscopy, and confocal microscopy. Together with the nontoxicity and excellent biocompatibility of the copolymer/SiO₂ composite, the features of controlled drug release and simultaneous carrier self‐destruction provided a promising opportunity for designing various novel drug‐delivery systems.     

All-Aqueous,Surfactant-Free,and pH-Driven Nanoformulation Methods of Dual-Responsive Polymer Nanoparticles and their Potential use as Nanocarriers of pH-Sensitive Drugs

All-aqueous, surfactant-free, and pH-driven nanoformulation methods to generate pH- and temperature-responsive polymer nanoparticles (NPs) are described. Copolymers comprising a poly(methyl methacrylate) (PMMA) backbone with a few units of 2-(dimethylamino)ethyl methacrylate (DMAEMA) are solubilized in acidic buffer (pH 2.0) to produce pH-sensitive NPs. Copolymers of different molar mass (2.3–11.5 kg mol⁻¹) and DMAEMA composition (7.3–14.2 mol%) are evaluated using a “conventional” pH-driven nanoformulation method (i.e., adding an aqueous polymer solution (acidic buffer) into an aqueous non-solvent (basic buffer)) and a robotized method for pH adjustment of polymer dispersions. Dynamic light scattering, zeta-potential (ζ), and sedimentation-diffusion analyses suggest the formation of dual-responsive NPs of tunable size (from 20 to 110 nm) being stable for at least 28 days in the pH and temperature intervals from 2.0 to 6.0 and 25 to 50 °C, respectively. Ultraviolet-visible spectroscopic experiments show that these NPs can act as nanocarriers for the pH-sensitive dipyridamole drug, expanding its bioavailability and potential controlled release as a function of pH and temperature. These approaches offer alternative strategies to prepare stimuli-responsive NPs, avoiding the use of harmful solvents and complex purification steps, and improving the availability of biocompatible polymer nanoformulations for specific controlled release of pH-sensitive cargos.     

Photoinduced Fluorescence Activation and Nitric Oxide Release with Biocompatible Polymer Nanoparticles

A viable strategy to encapsulate a fluorophore/photochrome dyad and a nitric oxide photodonor within supramolecular assemblies of a cyclodextrin‐based polymer in water was developed. The two photoresponsive guests do not interact with each other within their supramolecular container and can be operated in parallel under optical control. Specifically, the dyad permits the reversible switching of fluorescence on a microsecond timescale for hundreds of cycles, and the photodonor enables the irreversible release of nitric oxide. Furthermore, these supramolecular assemblies cross the membrane of human melanoma cancer cells and transport their cargo in the cytosol. The fluorescence of one component allows the visualization of the labeled cells, and its switchable character could, in principle, be used to acquire super‐resolution images, while the release of nitric oxide from the other induces significant cell mortality. Thus, our design logic for the construction of biocompatible nanoparticles with dual functionality might evolve into the realization of valuable photoresponsive probes for imaging and therapeutic applications.     

水热合成法对纳米氧化锡粉体粒径和形貌的控制研究

利用氯化锡和氨水作为反应试剂,通过水热合成技术制备了近球形,棒状,椭球形,六角形等粉体形貌和粒径范围从4 nm至120 nm的纳米氧化锡粉体,并对水热合成条件对粉体的粒径和形貌的影响进行了研究。所制备的粉体的XRD分析结果显示,合成温度在160 ℃以上并且合成时间在3 h以上,粉体全部具有氧化锡晶体结构。利用透射电镜对粉体的粒径和形貌观察发现,二氧化锡粉体的形貌和粒径可通过改变溶液的浓度,合成温度与合成时间进行有效的控制,其中合成温度与溶液浓度不仅可以控制合成粉体的粒径,而且可以控制粉体的形貌。     

Facile Fabrication of Thermo‐Responsive and Reduction‐Sensitive Polymeric Micelles for Anticancer Drug Delivery

The development of thermo‐responsive and reduction‐sensitive polymeric micelles based on an amphiphilic block copolymer poly[(PEG‐MEMA)‐co‐(Boc‐Cyst‐MMAm)]‐block‐PEG (denoted PEG‐P‐SS‐HP) for the intracellular delivery of anticancer drugs is reported. PTX, as model drug, was loaded into the PEG‐P‐SS‐HP micelles with an encapsulation efficiency >90%, resulting in a high drug loading content (up to 35 wt%). The PTX‐loaded PEG‐P‐SS‐HP micelles show slow drug release in PBS and rapid release after incubation with DTT. The PTX‐loaded micelles display a better cytotoxic effect than the free drug, whereas empty micelles are found to be non‐toxic. The thermo‐responsive and reduction‐sensitive polymeric micelles described may serve as promising carriers for cytostatic drugs.

     

Synthesis and Characterization of Polymer Brushes Containing β-Cyclodextrin Grafted to Magnetic Nanoparticles for Determination of Naproxen in Urine

β-Cyclodextrin containing polymer brushes were grafted to magnetic nanoparticles following free radical copolymerization of N,N-dimethylacrylamide and allyl glycidyl ether on the surface. The products were characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis, elemental analysis, and transmission electron microscopy and employed for solid phase extraction of naproxen in human urine. The profile of the naproxen adsorbed by the nanoparticles demonstrated high accessibility of the β-cyclodextrin. Scatchard analysis indicated that the capacity of the nanoparticles was 112 µmol g^?1 at 25°C and a pH of 5. The adsorption data of naproxen were considered by Langmuir, Freundlich, Redlich–Peterson, and Temkin isotherms. Approximately 55% of naproxen was released in simulated gastric fluid in 30 min and 94% in simulated intestinal fluid in 30 h. These data have indicated the utility of the naproxen loaded- β-cyclodextrin containing polymer brushes grafted to magnetic nanoparticles for enteric drug delivery.     

Crosslinked Poly(ionic liquid) Nanoparticles: Inner Structure,Size, and Morphology

In this contribution, we present the highly ordered inner structure of crosslinked poly(ionic liquid) nanoparticles. Cryogenic transmission electron microscopy revealed that they resembled centric multilamellar vesicles of different geometries, depending on the exact length of the quaternizing alkyl chains. The nanoparticle size was found to be sensitive to the polymerization conditions, such as the concentrations of monomers and crosslinking agents, the anion type and the externally added salt, but fairly inert to the polymerization temperature and the amount of initiator. The size expansion of the nanoparticles in different polymerization runs was found to be either isotropic or anisotropic via their linear attachment under certain polymerization conditions.