Molecularly imprinted cryogel as a pH-responsive delivery system for doxorubicin

In this study, implantable and degradable molecularly imprinted cryogel was prepared for pH-responsive delivery of doxorubicin. Cryogel discs were synthesized using amino acid-based functional monomer with HEMA and gelatin. The molecularly imprinted discs were characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, degradation and swelling tests. In vitro delivery experiments were carried out in order to examine the effects of medium pH and drug content. The degree of degradation of composite cryogels was found to be 83.45±1.86% after 56 days. The release profiles of DOX from molecularly imprinted cryogel discs exhibit a biphasic delivery. It was observed that an initial burst release step from 0 to 12 h was followed by a slower and sustained release. Release rate of DOX from cryogel discs increased in more acidic conditions. Kinetic studies showed that a combination of diffusion and erosion control is mainly responsible from the general release behaviors of molecularly imprinted cryogel discs.     

A novel dual thermo- and pH-responsive silver nanocomposite hydrogel as a drug delivery system

The purpose of this study was to develop a novel dual thermo- and pH-responsive silver nanocomposite hydrogel (SNH) for drug release applications. This smart SNH was prepared in a facile one-pot method by in situ reduction of silver ions in salep solution and then grafting of poly(vinylpyrrolidone-co-acrylic acid) onto it. The SNH was characterized by transmission electron microscopy (TEM), scanning electron microscopy with energy-dispersive X-ray analysis (SEM–EDAX), thermo-gravimetric analysis (TGA), Fourier transform infrared (FT-IR), UV–Vis spectroscopy, and cyclic voltammetry. The dependence of swelling properties of the prepared SNH on the reaction variables (such as monomer, Ag NO₃, and cross-linker concentrations), temperature, pH, and salt was investigated. The potential of obtained SNH was examined for the deferasirox release from prepared hydrogel under different temperatures and pHs. The evaluation of release mechanism and determination of diffusion coefficients were also studied. In addition, SNH showed good antibacterial potentials. The results of this study provide valuable information regarding the development of dual stimuli-sensitive SNH for biomedical applications.     

Thiol modified chitosan-silica nanohybrid for antibacterial,antioxidant and drug delivery application

Chitosan exhibits great versatility in various biomedical fields and mesoporous silica nanoparticles have emerged as an interesting material in biomedical areas owing to their outstanding physio-chemical properties. The combination of inorganic silica and organic polymer such as chitosan, make them suitable for a wide range of biomedical applications. Here, we have explored the benefits of chitosan and silica by synthesizing chitosan-silica nanohybrid. In the synthesis of chitosan-silica (CS–Si) nanohybrid, chitosan is modified by thioglycolic acid and mesoporous silica MCM-41(Mobil Composition of Matter number 41) is functionalized by 3-(trimethoxysilyl)-1-propane thiol (TMSP). The modified chitosan and thiol functionalized MCM-41(inorganic network) is then linked through disulfide bond by oxidation process or oxidative coupling, resulting in the formation of inorganic-organic hybrid material. The hybrid material was characterized by FTIR, Raman, XRD, TGA, Zeta potential, EDX, Proton NMR and SEM techniques. The antibacterial results indicated that gram-negative (E. coli) bacteria exhibit better inhibition zone than gram-positive (B. subtilis) bacteria. The DPPH scavenging capability of synthesized hybrid was found to be 68%. The drug (quercetin) encapsulation efficiency of hybrid material was calculated to be 92.38% and more drug releases in acidic medium (pH 5.0) than at pH 7.4, so we can conclude that hybrid material shows pH-dependent drug releasing behavior. The results show that synthesized nano-hybrid material possess good antibacterial and antioxidant activities and is also a good nanocarrier for drug delivery application.     

Acid-degradable solid-walled microcapsules for pH-responsive burst-release drug delivery

Acid-degradable microcapsules were prepared via an interfacial polymerization. Degradation of the thin wall of the capsules leads to all-or-nothing cargo release. The only byproducts of degradation are acetone, and a non-toxic triamide. Proof-of-concept experiments showed that cargo can be delivered to and released in cells.     

pH-responsive lyotropic liquid crystals for controlled drug delivery

We present a food-grade lyotropic liquid crystal system, capable of responding to pH variations with a reversible switch in both the structure and physical properties. The system, which is composed by monolinolein and linoleic acid (97:3 wt % ratio) in the presence of excess water at 37 °C and 150 mM ionic strength, is specifically designed to reversibly change from a Im3m reverse bicontinuous cubic phase to a H(II) reverse columnar hexagonal phase, when changing the pH from neutral (pH 7) to acidic (pH 2) conditions, to simulate intestine and stomach conditions, respectively. The pH responsiveness is provided by the linoleic acid, which, being a weak acid (pK(a) ≈ 5), is essentially in the deprotonated charged state at pH 7 and mainly protonated and neutral at pH 2, imposing changes in the critical packing parameter (CPP) of the lyotropic liquid crystal. The use of this system as an efficient controlled-release delivery vehicle is demonstrated on the model hydrophilic drug phloroglucinol, by both release and diffusion studies at different pH, as followed by ultraviolet-visible (UV-vis) spectroscopy. The Im3m cubic phase at pH 7 is shown to release 4 times faster than the H(II) phase at pH 2, making this system an ideal candidate for oral administration of drugs for targeted delivery in intestine or colon tracts.     

Construction of a pH-responsive drug delivery platform based on the hybrid of mesoporous silica and chitosan

Mesoporous silica nanoparticles (MSN) have been widely used for drug delivery due to their large specific surface area and excellent biocompatibility. However, the mesoporous structure of MSN would lead to the inevitable “premature release” of the drugs, and therefore the modification of MSN for controlled delivery seems to be a necessary step. Herein, chitosan (CS) was used for the surface functionalization of MSN via amidation reaction, and the introduced CS could function as a “gatekeeper” and the drug of methotrexate (MTX) might be encapsulated in the mesopores of MSN. As a result, the “premature release” of the encapsulated MTX could be effectively circumvented with the aid of the CS cap. More importantly, the drug delivery from the hybrid of MSN and CS (MSN/CS) can be endowed with pH-sensitivity by the introduction of CS because the amide bonding between CS and MSN is highly pH-sensitive. The cumulative release of MTX from the MSN/CS is more pronounced at pH 5.0 (80.86%) than those at pH 6.8 (40.46%) and pH 7.4 (18.25%).     

Synthesis and characterization of a starch‐modified hydrogel as potential carrier for drug delivery system

Synthesis and characterization of a new hydrogel were carried out using a chemically modified starch (starch‐M) consisting of coupling C?C bounds coming from glycidil methacrylate (GMA) onto the polysaccharide structure. ¹³C NMR, ¹H NMR, and FT‐IR spectroscopies were used to confirm the incorporation of such groups onto the starch‐M. The hydrogel was prepared by a crosslinking polymerization of starch‐M using sodium persulfate as an initiating agent. The starch‐M hydrogel shows morphology clearly different from that of the raw starch film due to the presence of voids on its surface. The swelling process of the starch‐M hydrogel was not significantly affected by changes on the temperature or on pH of the surrounding liquid, indicating the such behavior can be then understood by a diffusional process, resulting from its physical–chemical interactions with the solvent. The values of the diffusional exponent n were on the order of 0.45–0.49 for the range of pHs investigated, demonstrating that the water transport mechanism of starch‐M hydrogel is more dependent on Fickian diffusion, that is, controlled by water diffusion. Such starch‐M hydrogel is a promising candidate to be used in transporting and in preserving acid‐responsive drugs, such as corticoids, for the treatment of colon‐specific diseases, for example, Crohn's disease. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 2567–2574, 2008     

Aptamer-based self-assembled supramolecular vesicles for pH-responsive targeted drug delivery

Supramolecular vesicles have received great attention in biomedical application due to their inherent features, including simple synthesis and tunable amphiphilicity of the building blocks. Despite tremendous research efforts, developing supramolecular vesicles with targeted recognition and controlled release remains a major challenge. Herein, we constructed a novel aptamer-based self-assembled supramolecular vesicle by host-guest complexation of pyrene, viologen lipid, and cucurbit[8]urils for pH-responsive and targeted drug delivery. The proposed supramolecular vesicles are easy to be assembled and offer simple drug loading. Based on confocal fluorescence microscopy and cytotoxicity experiments, the drug-loaded supramolecular vesicles were shown to possess highly efficient internalization and apparent cytotoxic effect on target cancer cells, but not control cells. Furthermore, through simple aptamer or drug substitution, supramolecular vesicles can be applied to a variety of target cell lines and drugs, making it widely applicable. Taking advantage of the easy preparation, good stability, rapid pH response, and cell targeting ability, the aptamer-based self-assembled supramolecular vesicles hold great promise in controlled-release biomedical applications and targeted cancer therapy.     

Synthesis of a biodegradable polymeric supramolecular assembly for drug delivery

A novel design of a biodegradable carrier for drug delivery was established by constructing a supramolecular assembly of drugs and polymer backbones without any covalent bonds. A biodegradable polyrotaxane was synthesized in which α-cyclodextrins (α-CDs) as drug carriers were threaded onto poly(ethylene glycol) chains which then were capped at each chain end by L -phenylalanine via peptide linkages. The release of α-CDs was observed only when the terminal peptide linkages were degraded.     

Coordination bonding based pH-responsive albumin nanoparticles for anticancer drug delivery

Zn-loaded bovine serum albumin nanoparticles (Zn-BSA nanoparticles) were prepared and used as carriers for pH-responsive anticancer drug delivery. Zinc was introduced into this system to increase the stability of the BSA nanoparticles and to load the anticancer drug based on the coordination bonding formation of Zn-BSA and Zn-drug molecules, respectively. The cleavage of either the "Zn-BSA" or the "Zn-drug" coordination bonding, in response to pH, would result in the release of the drug under designated pH conditions. The nanoparticles were spherical with diameters of 50-60 nm and narrow size distribution. Mitoxantrone (MX) was chosen as the model drug to study the release behavior and the inhibitory efficacy against tumor cells. In vitro release behavior of MX loaded Zn-BSA nanoparticles (MX-Zn-BSA nanoparticles) showed a fine pH-responsiveness. The release amount at pH 5.0 was close to 80%, while the cumulative release amount at pH 7.4 was less than 6% within 24 h. The blank Zn-BSA nanoparticles were of low cytotoxicity, while a high cytotoxic activity of MX-Zn-BSA nanoparticles against MCF-7 cells was demonstrated by in vitro cell assays.     

Targeted pH-responsive polyion complex micelle for controlled intracellular drug delivery

Cancer therapy with nanoscale drug formulations has made significant progress in the past few decades. However, the selective accumulation and release of therapeutic agents in the lesion sites are still great challenges. To this end, we developed a cRGD-decorated pH-responsive polyion complex (PIC) micelle for intracellular targeted delivery of doxorubicin (DOX) to upregulate tumor inhibition and reduce toxicity. The PIC micelle was self-assembled via the electrostatic interaction between the positively charged cRGD-modified poly(ethylene glycol)-block-poly(l-lysine) and the anionic acid-sensitive 2,3-dimethylmaleic anhydride-modified doxorubicin (DAD). The decoration of cRGD enhanced the cell internalization of PIC micelle through the specific recognition of α_vβ₃ integrin on the membrane of tumor cells. The active DOX was released under intracellular acidic microenvironment after endocytosis following the decomposition of DAD. Moreover, the targeted PIC micelle exhibited enhanced inhibition efficacies toward hepatoma in vitro and in vivo compared with the insensitive controls. The smart multifunctional micelle provides a promising platform for target intracellular delivery of therapeutic agent in cancer therapy.     

pH-responsive hollow core zeolitic-imidazolate framework-8 as an effective drug carrier of 5-fluorouracil

To enhance the porosity and accessibility, a novel drug carrier, the hollow core zeolitic-imidazolate framework-8 (HZIF-8), is designed using polystyrene as a hard template to sequentially load and release 5-fluorouracil (FU). HZIF-8 is signified by a large surface area and pore volume, reaching 1727.1 m²/g and 0.99 cm³/g, respectively. The obtained HZIF-8 exhibits rhombic dodecahedron morphology with a uniform particle size of 450 nm. The integrated hollow core is observed at ca. 180 nm. Evaluation of the FU encapsulation behavior in HZIF-8 nanospheres is demonstrated via the adsorption kinetics, isotherm, and thermodynamic studies. The maximum FU uptake is monitored at 40 °C with the loading capacity of 161.9 mg/g. This study suggests that the FU uptake follows the pseudo-second-order law and multilayer mechanism. The governing mechanism is chemical binding in its first layer and physical interaction in the upper layers. The release study of FU from FU-loaded HZIF-8 shows that the cumulative release at pH 5.5 (92.03%) is four times higher than that at pH 7.4 (23.31%), indicating a stimulus-responsive release mechanism where pH is required as an internal stimulus factor.     

Facile preparation of pH-responsive PEGylated prodrugs for activated intracellular drug delivery

The acid-cleavable amphiphilic prodrug DOX-PEG-DOX self-assemble to form nanoparticles and enter the cell by endocytosis for the pH-triggered intracellular delivery of DOX.     

Facile preparation of pH-responsive PEGylated prodrugs for activated intracellular drug delivery

PEGylated prodrug, covalent attaching polyethylene glycol (PEG) polymer chains to therapeutic drugs, is one of the most promising techniques to improve the water-solubility, stability, and therapeutic effect of drugs. In this study, three PEGylated acid-sensitive prodrugs DOX-PEG-DOX with different molecular weights, were prepared via Schiff-base reaction between aldehyde-modified PEG and the amino groups of doxorubicin (DOX). This kind of amphiphilic polymeric prodrug could be self-assemble into nanoparticles in aqueous solution. The average particle size and morphologies of the prodrug nanoparticles under different pH conditions were observed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. It turned out that the nanoparticles could be kept stable in the physiological environment, but degraded in acidic medium. Subsequently, we also investigated in vitro drug release behavior and found that the prodrug had acid-sensitive property. The cytotoxicity and intracellular uptake assays revealed that the prodrugs could rapidly internalized by HeLa or HepG2 cells to release DOX and effectively inhibited the proliferation of the tumor cells, which have the potential for use in cancer therapy.     

Catechol polymers for pH-responsive, targeted drug delivery to cancer cells

A novel cell-targeting, pH-sensitive polymeric carrier was employed in this study for delivery of the anticancer drug bortezomib (BTZ) to cancer cells. Our strategy is based on facile conjugation of BTZ to catechol-containing polymeric carriers that are designed to be taken up selectively by cancer cells through cell surface receptor-mediated mechanisms. The polymer used as a building block in this study was poly(ethylene glycol), which was chosen for its ability to reduce nonspecific interactions with proteins and cells. The catechol moiety was exploited for its ability to bind and release borate-containing therapeutics such as BTZ in a pH-dependent manner. In acidic environments, such as in cancer tissue or the subcellular endosome, BTZ dissociates from the polymer-bound catechol groups to liberate the free drug, which inhibits proteasome function. A cancer-cell-targeting ligand, biotin, was presented on the polymer carriers to facilitate targeted entry of drug-loaded polymer carriers into cancer cells. Our study demonstrated that the cancer-targeting drug-polymer conjugates dramatically enhanced cellular uptake, proteasome inhibition, and cytotoxicity toward breast carcinoma cells in comparison with nontargeting drug-polymer conjugates. The pH-sensitive catechol-boronate binding mechanism provides a chemoselective approach for controlling the release of BTZ in targeted cancer cells, establishing a concept that may be applied in the future toward other boronic acid-containing therapeutics to treat a broad range of diseases.     

Modified MCM-41 as a drug delivery system for acetylsalicylic acid

The modification of prepared MCM-41 by different groups (amino, chloro and oxo) was studied. Prepared materials were treated by acetylsalicylic acid and hybrid materials were characterized, compared from the point of view of immobilized amount of active substance. The highest amount of acetylsalicylic acid was detected using methyl-tert- butyl ether as a solvent and MCM-41 without modification after 1 h (0.35 g per 1 g of the support) or MCM modified by amino group after 5 h (0.37 g per 1 g of the support) as a support. Using amino modified MCM, the longer treatment by acetylsalicylic acid converged to the equilibrium and after 24 h the immobilized amount was 0.3 g per 1 g. A dissolution in vitro study was carried out, comparing the stability of formed interactions. The slowest dissolution was detected using non-modified MCM-41 and oxo modified material.     

Synthesis of self-assemble pH-responsive cyclodextrin block copolymer for sustained anticancer drug delivery

Well-defined p H-responsive poly(ε-caprolactone)-graft-β-cyclodextrin-graft-poly(2-(dimethylamino)ethylmethacrylate)-co-poly(ethylene glycol) methacrylate amphiphilic copolymers(PCL-g-β-CD-g-P(DMAEMA-co-PEGMA)) were synthesized using a combination of atom transfer radical polymerization(ATRP),ring opening polymerization(ROP) and "click" chemistry.Successful synthesis of polymers was confirmed by Fourier transform infrared spectroscopy(FTIR),proton nuclear magnetic resonance(1H-NMR),and gel permeation chromatography(GPC).Then,the polymers could selfassemble into micelles in aqueous solution,which was demonstrated by dynamic light scattering(DLS) and transmission electron microscopy(TEM).The p H-responsive self-assembly behavior of these copolymers in water was investigated at different p H values of 7.4 and 5.0 for controlled doxorubicin(DOX) release,and these results revealed that the release rate of DOX could be effectively controlled by altering the p H,and the release of drug loading efficiency(DLE) was up to 88%(W/W).CCK-8 assays showed that the copolymers had low toxicity and possessed good biodegradability and biocompatibility,whereas the DOX-loaded micelles remained with high cytotoxicity for He La cells.Moreover,confocal laser scanning microscopy(CLSM) images revealed that polymeric micelles could actively target the tumor site and the efficient intracellular DOX release from polymeric micelles toward the tumor cells further confirmed the anti-tumor effect.The DOX-loaded micelles could easily enter the cells and produce the desired pharmacological action and minimize the side effect of free DOX.These results successfully indicated that p H-responsive polymeric micelles could be potential hydrophobic drug delivery carriers for cancer targeting therapy with sustained release.