Surface diffusion driven nanoshell formation by controlled sintering of mesoporous nanoparticle aggregates

We report a general method for the synthesis of hollow structures of a variety of functional inorganics by partial sintering of mesoporous nanocrystal aggregates. The formation of a thin shell initiates the transport of mass from the interior leading to growth of the shell. The principles are general and the hollow structures thus produced are attractive for many applications including catalysis, drug delivery and biosensing.

Magnetically actuated propulsion at low Reynolds numbers: towards nanoscale control

Significant progress has been made in the fabrication of micron and sub-micron structures whose motion can be controlled in liquids under ambient conditions. The aim of many of these engineering endeavors is to be able to build and propel an artificial micro-structure that rivals the versatility of biological swimmers of similar size, e. g. motile bacterial cells. Applications for such artificial ``micro-bots'' are envisioned to range from microrheology to targeted drug delivery and microsurgery, and require full motion-control under ambient conditions. In this Mini-Review we discuss the construction, actuation, and operation of several devices that have recently been reported, especially systems that can be controlled by and propelled with homogenous magnetic fields. We describe the fabrication and associated experimental challenges and discuss potential applications.

Nanoporous alloy aggregates: synthesis and electrocatalytic activity

Nanoporous structures are widely used for many applications and hence there have been several efforts directed towards their synthesis. While several template-based and template-less approaches are available for monometallic systems, there is no general method for the synthesis of nanoporous multicomponent systems/alloys. We present a general template-less strategy for the synthesis of nanoporous alloy aggregates by controlled aggregation of nanoparticles in the solution phase with excellent control over morphology and composition as illustrated using AuPt, AuPd, PdPt and PtRu systems as examples. The Pt-based nanoporous clusters exhibit excellent activity for methanol oxidation with good long-term stability and CO tolerance. We show that the method can be extended to produce ternary catalysts and hence we expect our method to be widely used for the synthesis of multifunctional nanoporous structures for catalysis, sensor and drug-delivery applications.

Formulation development and evaluation of lamivudine controlled release tablets using cross-linked sago starch

Objectives: Modified starches based polymeric substances find utmost applicability in pharmaceutical formulation development. Cross-linked starches showed very promising results in drug delivery application. The present investigation concerns with the development of controlled release tablets of lamivudine using cross-linked sago starch. Methods: The cross-linked derivative was synthesized with phosphorous oxychloride and native sago starch in basic pH medium. The cross-linked sago starch was tested for acute toxicity and drug-excipient compatibility study. The formulated tablets were evaluated for various physical characteristics, in vitro dissolution release study and in vivo pharmacokinetic study in rabbit model. Results: In vitro release study showed that the optimized formulation exhibited highest correlation (R) in case of zero order kinetic model and the release mechanism followed a combination of diffusion and erosion process. There was a significant difference in the pharmacokinetic parameters (T-max, C-max, AUC, V-d, T-1/2, and MDT) of the optimized formulation as compared to the marketed conventional tablet Lamivir (R). Conclusion: The cross-linked starch showed promising results in terms of controlling the release behavior of the active drug from the matrix. The hydrophilic matrix synthesized by cross-linking could be used with a variety of active pharmaceutical ingredients for making their controlled/sustained release formulations.

Protamine-Capped Mesoporous Silica Nanoparticles for Biologically Triggered Drug Release

The fabrication of a mesoporous silica nanoparticle (MSN)-protamine hybrid system (MSN-PRM) is reported that selectively releases drugs in the presence of specific enzyme triggers present in the proximity of cancer cells. The enzyme trigger involved is a protease called trypsin, which is overexpressed in certain specific pathological conditions, such as inflammation and cancer. Overexpression of trypsin is known to be associated with invasion, metastasis, and growth in several cancers, such as leukemia, colon cancer, and colorectal cancer. The current system (MSN-PRM) consists of an MSN support in which mesopores are capped with an FDA-approved peptide drug protamine, which effectively blocks the outward diffusion of the drug molecules from the mesopores of the MSNs. On exposure to the enzyme trigger, the protamine cap disintegrates, opening up the molecular gates and releasing the entrapped drug molecules. The system exhibits minimal premature release in the absence of the trigger and selectively releases the encapsulated drugs in the presence of the proteases secreted by colorectal cancer cells. The ability of the MSN-PRM particles to deliver anticancer drugs to colorectal cancer cells has also been demonstrated. The hydrophobic drug is released into cancer cells subsequent to disintegration of the protamine cap, resulting in cell death. Drug-induced cell death in colorectal cancer cells is significantly enhanced when the hydrophobic drug that is known to degrade in aqueous environments is encapsulated in the MSN-PRM system in comparison to the free drug (P < 0.05). The system, which shows good biocompatibility and selective drug release, is a promising platform for cancer specific drug delivery.

Conformal Cytocompatible Ferrite Coatings Facilitate the Realization of a Nanovoyager in Human Blood

Controlled motion of artificial nanomotors in biological environments, such as blood, can lead to fascinating biomedical applications, ranging from targeted drug delivery to microsurgery and many more. In spite of the various strategies used in fabricating and actuating nanomotors, practical issues related to fuel requirement, corrosion, and liquid viscosity have limited the motion of nanomotors to model systems such as water, serum, or biofluids diluted with toxic chemical fuels, such as hydrogen peroxide. As we demonstrate here, integrating conformal ferrite coatings with magnetic nanohelices offer a promising combination of functionalities for having controlled motion in practical biological fluids, such as chemical stability, cytocompatibility, and the generated thrust. These coatings were found to be stable in various biofluids, including human blood, even after overnight incubation, and did not have significant influence on the propulsion efficiency of the magnetically driven nanohelices, thereby facilitating the first successful ``voyage'' of artificial nanomotors in human blood. The motion of the ``nanovoyager'' was found to show interesting stick-slip dynamics, an effect originating in the colloidal jamming of blood cells in the plasma. The system of magnetic ``nanovoyagers'' was found to be cytocompatible with C2C12 mouse myoblast cells, as confirmed using MTT assay and fluorescence microscopy observations of cell morphology. Taken together, the results presented in this work establish the suitability of the ``nanovoyager'' with conformal ferrite coatings toward biomedical applications.

Protamine-carboxymethyl cellulose magnetic nanocapsules for enhanced delivery of anticancer drugs against drug resistant cancers

Multidrug resistance is a major therapeutic challenge faced in the conventional chemotherapy. Nanocarriers are beneficial in the transport of chemotherapeutics by their ability to bypass the P-gp efflux in cancers. Most of the P-gp inhibitors under phase II clinical trial are facing failures and hence there is a need to develop a suitable carrier to address P-gp efflux in cancer therapy. Herein, we prepared novel protamine and carboxymethyl cellulose polyelectrolyte multi-layered nanocapsules modified with Fe3O4 nanoparticles for the delivery of doxorubicin against highly drug resistant HeLa cells. The experimental results revealed that improved cellular uptake, enhanced drug intensity profile with greater percentage of apoptotic cells was attained when doxorubicin loaded magnetic nanocapsules were used in the presence of external magnetic field. Hence, we conclude that this magnetic field assisted nanocapsule system can be used for delivery of chemotherapeutics for potential therapeutic efficacy at minimal dose in multidrug resistant cancers. From the Clinical Editor: Many cancer drugs fail when cancer cells become drug resistant. Indeed, multidrug resistance (MDR) is a major therapeutic challenge. One way that tumor cells attain MDR is by over expression of molecular pumps comprising of P-glycoprotein (P-gp) and multidrug resistant proteins (MRP), which can expel chemotherapeutic drugs out of the cells. In this study, the authors prepared novel protamine and carboxymethyl cellulose polyelectrolyte multi-layered nanocapsules modified with Fe3O4 nanoparticles for the delivery of doxorubicin. The results show that there was better drug delivery and efficacy even against MDR tumor cells. (C) 2015 Elsevier Inc. All rights reserved.

Dual Drug Conjugate Loaded Nanoparticles for the Treatment of Cancer

Two antineoplastic agents, Imatinib (IM) and 5-Fluorouracil (FU) were conjugated by hydrolysable linkers through an amide bond and entrapped in polymeric Human Serum Albumin (HSA) nanoparticles. The presence of dual drugs in a common carrier has the advantage of reaching the site of action simultaneously and acting at different phases of the cell cycle to arrest the growth of cancer cells before they develop chemoresistance. The study has demonstrated an enhanced anticancer activity of the conjugate, and conjugate loaded stealth HSA nanoparticles (NPs) in comparison to the free drug in A-549 human lung carcinoma cell line and Zebra fish embryos (Danio rerio). Hydrolysability of the conjugate has also been demonstrated with complete hydrolysis being observed after 12 h. In vivo pharmacodynamics study in terms of tumor volume and pharmacokinetics in mice for conjugate (IM-SC-FU) and conjugate loaded nanoparticles showed significant anti-cancer activity. The other parameters evaluated were particle size (86nm), Poly Dispersive Index (PDI) (0.209), zeta potential (-49mV), drug entrapment efficiency (96.73%) and drug loading efficiency (89%). Being in stealth mode gives the potential for the NPs to evade Reticulo-Endothelial system (RES), achieve passive targeting by Enhanced Permeation Retention (EPR) effect with controlled release of the therapeutic agent. As the conjugate cleaves into individual drugs in the tumor environment, this promises better suppression of cancer chemoresistance by delivering dual drugs with different modes of action at the same site, thereby synergistically inhibiting the growth of cancerous tissue.

Temperature-and pH-Sensitive Nanohydrogels of Poly(N-Isopropylacrylamide) for Food Packaging Applications: Modelling the Swelling-Collapse Behaviour

Temperature-sensitive poly(N-isopropylacrylamide) (PNIPA) nanohydrogels were synthesized by nanoemulsion polymerization in water-in-oil systems. Several cross-linking degrees and the incorporation of acrylic acid as comonomer at different concentrations were tested to produce nanohydrogels with a wide range of properties. The physicochemical properties of PNIPA nanohydrogels, and their relationship with the swelling-collapse behaviour, were studied to evaluate the suitability of PNIPA nanoparticles as smart delivery systems (for active packaging). The swelling-collapse transition was analyzed by the change in the optical properties of PNIPA nanohydrogels using ultraviolet-visible spectroscopy. The thermodynamic parameters associated with the nanohydrogels collapse were calculated using a mathematical approach based on the van't Hoff analysis, assuming a two-state equilibrium (swollen to collapsed). A mathematical model is proposed to predict both the thermally induced collapse, and the collapse induced by the simultaneous action of two factors (temperature and pH, or temperature and organic solvent concentration). Finally, van't Hoff analysis was compared with differential scanning calorimetry. The results obtained allow us to solve the problem of determining the molecular weight of the structural repeating unit in cross-linked NIPA polymers, which, as we show, can be estimated from the ratio of the molar heat capacity (obtained from the van't Hoff analysis) to the specific heat capacity (obtained from calorimetric measurements).

5-氟尿嘧啶-β-环糊精结肠靶向前体药物的研究

5-氟尿嘧啶(5-Fluorouracil， 5-FU)是一种抗代谢药物，广泛用于临床治疗结直肠癌、胃癌、乳腺癌等多种癌症，但其首过代谢显著、亲脂性较低，选择性差、毒副作用大。为克服这些缺点人们对5-FU进行了大量的修饰工作，包括小分子修饰以及与各种载体形成微球、微囊、纳米粒、共价前药等。 环糊精(Cyclodextrin，简称CD)，可被结肠中的糖苷酶特异性地降解成小分子糖，而胃和小肠中由于缺乏相应的酶而使环糊精不被降解，这一特性在结肠药物的靶向输送及释放中有重要应用价值。环糊精中含有丰富的羟基，易进行化学修饰，将药物与环糊精通过共价键结合制成前药，使其在胃和小肠中不降解，而在盲结肠中被特异性的酶降解释出药物，达到结肠靶向释药的目的。研究表明，环糊精作为一种前药载体为结肠靶向释药和缓释、控释系统提供了一种有效的手段。 本工作选择5-氟尿嘧啶为模型药物、β-环糊精作为载体，通过中间体5-FU羧酸衍生物的制备及其与β-环糊精的偶联，合成了系列5-FU-β-CD前体药物，并利用紫外、红外、质谱、核磁、元素分析、热分析等手段对其进行结构表征。同时，还研究了前体药物的体外释药性质。具体内容包括： 1. 含有羧基的5-FU衍生物中间体的合成：(5-氟尿嘧啶-1-基)-乙酸(FUAC)、3-(5-氟尿嘧啶-1-基)-丙酸(FUPC)、5-(5-氟尿嘧啶-1-基)-戊酸(FUVC)的合成。 2. 中间体5-FU的羧酸衍生物与β-CD的偶联：分别通过以6-OTs-β-CD为中间体的取代法和活化酯法，合成了第一面取代和第二面取代的5-FU-β-CD大分子前体药物。在二面取代的前体药物制备中，通过改变原料的比例，合成了系列不同取代度(DS)的2-[(5-氟尿嘧啶-1-基)-乙酰基] -β-环糊精结合物。 3. 对上述前体药物进行体外释放研究：分别考察了前体药物在不同pH缓冲溶液中的水解行为及其在小鼠胃肠道人工体液中的酶解行为，并通过UV-Vis及HPLC对前体药物释放情况进行检测分析。 5-Fluorouracil(5-Fu), commonly known as a broad-spectrum antineoplastic drug, has been widely used in the treatment of various kinds of cancer including colon cancer for 40 years. However, this antitumor agent exhibits serious adverse effects, such as their marrow toxicity, gastrointestinal reaction and low selectivity in their clinical use. In order to improve its antitumor activity and reduce its toxicity, the compound was modified in various ways, including the formation of conjugated prodrugs with kinds of carrier, microsphere and nanoparticles etc. Cyclodextrins(CDs) are known to be barely capable of being hydrolyzed and only slightly absorbed in passing through the stomach and small intestine; however they are fermented into small saccharides by colonic microflora and thus absorbed as small saccharides in the large intestine. This biodegradation property of CDs may be useful as a colon-targeting carrier, and thus CD prodrugs may serve as a source of site-specific delivery of drugs to colon. It was demonstrated that prodrugs of CDs can provide a versatile means for construction of not only colon targeted delivery systems, but also delayed release systems. 5-Fluorouracil was taken as a model drug and β-CD as the carrier in this study. Series prodrugs of 5-FU was prepared through the preparation of reactive 5-FU derivatives containing carboxyl group and coupling to hydroxyl groups of CD. The structures of the conjugates were charactered by using IR, UV–vis, ESI-MS, 1H, 13C-NMR spectra, elemental analyses, and thermal analysis. In vitro hydrolysis behavior in aqueous solution and in rat gastrointestinal tract contents of the conjugates were also investigated. The main content of this dissertation includes following aspects: 1. The preparation of 5-FU derivatives containing carboxyl group: 5-Fluorouracil- acetic acid(FUAC)、3-(5-FU-1)-propionic acid (FUPC)、and 5-(5-FU-1)-valeric acid(FUVC). 2. The coupling of 5-FU derivatives to β-CD: 5-FU was selectively conjugated onto the primary or secondary hydroxyl groups of β-CD through an ester linkage, by the substitution of 6-OTs-β-CD and the activated ester method respectively. For the secondary face conjugation, the degree of substitution(DS) can be controlled by changing the mole ratio of the starting materials(FUAC and β-CD). 3. In vitro release behavior of the conjugates in aqueous solution and in rat gastro- intestinal tract contents of the conjugates were investigated, and the reaction was monitored and analyzed by using UV-Vis and HPLC methods.

Bioactive, Luminescent and Mesoporous Europium-doped Hydroxyapatite as a Drug Carrier

Bioactive, luminescent and mesoporous europium-doped hydroxyapatite (Eu:HAp) was successfully prepared through a simple one-step route using cationic surfactant as template. The obtained multifunctional hydroxyapatite was performed as a drug delivery carrier to investigate the drug storage/release properties using ibuprofen (IBU) as a model drug

Luminescent and Mesoporous Europium-Doped Bioactive Glasses (MBG) as a Drug Carrier

Luminescent and mesoporous europium-doped bioactive glasses (MBG:Eu) were successfully synthesized by a two-step acid-catalyzed self-assembly process combined with hydrothermal treatment in an inorganic-organic system. The obtained MBG was performed as a drug delivery carrier to investigate the drug storage/release properties using ibuprofen (IBU) as a model drug. The structural, morphological, textural and optical properties were well characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), N-2 adsorption/desorption, and photoluminescence (PL) spectra, respectively. The results reveal that the MBG exhibit the typical ordered characteristics of the hexagonal mesostructure. This composite shows sustained release profile with ibuprofen as the model drug. The IBU-loaded samples still show red luminescence of Eu3+ (D-5(0)-F-7(1, 2)) under UV irradiation, and the emission intensities of Eu3+ in the drug carrier system vary with the released amount of IBU, thus making the drug release be easily tracked and monitored by the change of the luminescence intensity.

Biodegradable amphiphilic polymer-drug conjugate micelles

The coupling of drugs to macromolecular carriers received an important impetus from Ringsdorf's notion of polymer-drug conjugates. Several water-soluble polymers, poly(ethylene glycol), poly[N-(2-hydroxypropyl) methacrylamidel, poly(L-glutamic acid) and dextran, are studied intensively and have been utilized successfully in clinical research. The promising results arising from clinical trials with polymer-drug conjugates (e.g., paclitaxel, doxorubicin, camptothecins) have provided a firm foundation for other synthetic polymers, especially biodegradable polymers, used as drug delivery vehicles. This review discusses biodegradable polymeric micelles as an alternative drug-conjugate system. Particular focus is on A-B or B-A-B type biodegradable amphiphilic block copolymer such as polylactide, morpholine-2,5-dione derivatives and cyclic carbonates, which can form a core-shell micellar structure, with the hydrophobic drug-binding segment forming the hydrophobic core and the hydrophilic segment as a hydrated outer shell. Polymeric micelles can be designed to avoid uptake by cells of reticuloendothelial system and thus enhance their blood lifetime via the enhanced permeability and retention effect.

Synthesis and characterization of photo-cross-linked hydrogels based on biodegradable polyphosphoesters and poly(ethylene glycol) copolymers

Novel biodegradable hydrogels by photo-cross-linking macromers based on polyphosphoesters and poly(ethylene glycol) (PEG) are reported. Photo-cross-linkable macromers were synthesized by ring-opening polymerization of the cyclic phosphoester monomer 2-(2-oxo-1,3,2-dioxaphospholoyloxy) ethyl methacrylate (OPEMA) using PEG as the initiator and stannous octoate as the catalyst. The macrorners were characterized by H-1 NMR, Fourier transform infrared spectroscopy, and gel permeation chromatography measurements. The content of polyphosphoester in the macromer was controlled by varying the feed ratio of OPEMA to PEG. Hydrogels were fabricated by exposing aqueous solutions of macromers with 0.05% (w/w) photoinitiator to UV light irradiation, and their swelling kinetics as well as degradation behaviors were evaluated. The results demonstrated that cross-linking density and pH values strongly affected the degradation rates. The macromers was compatible to osteoblast cells, not exhibiting significant cytotoxicity up to 0.5 mg/mL. "Live/dead" cell staining assay also demonstrated that a large majority of the osteoblast cells remained viable after encapsulation into the hydrogel constructs, showing their potential as tissue engineering scaffolds.