Doxorubicin-conjugated mesoporous magnetic colloidal nanocrystal clusters stabilized by polysaccharide as a smart anticancer drug vehicle

Fabrication of magnetic nanocarriers that demonstrate enhanced biocompatibility and excellent colloidal stability is critical for the application of magnetic-motored drug delivery, and it remains a challenge. Herein, a novel approach to synthesize mesoporous magnetic colloidal nanocrystal clusters (MMCNCs) that are stabilized by agarose is described; these clusters demonstrate high magnetization, large surface area and pore volume, excellent colloidal stability, enhanced biocompatibility, and acid degradability. The hydroxyl groups of agarose, which cover the surface of the magnetic nanocrystals, are modified with vinyl groups, followed by click reaction with mercaptoacetyl hydrazine to form the terminal hydrazide (-CONHNH(2) ). The anticancer agent doxorubicin (DOX) is then conjugated to MMCNCs through a hydrazone bond. The resulting hydrazone is acid cleavable, thereby providing a pH-sensitive drug release capability. This novel carrier provides an important step towards the construction of a new family of magnetic-motored drug-delivery systems. The experimental results show that the release rate of DOX from the DOX-conjugated MMCNCs (MMCNCs-DOX) is dramatically improved at low pH (tumor cell: pH 4-5 in the late stage of endolysosome and pH 5-6 from the early to late endosome), while almost no DOX is released at neutral pH (blood plasma). The cell cytotoxicity of the MMCNCs-DOX measured by MTT assay exhibits a comparable antitumor efficacy but lower cytotoxicity for normal cell lines, when measured against the free drug, thus achieving the aim of reducing side effects to normal tissues associated with controlled drug release.     

Doxorubicin-loaded polymeric micelle overcomes multidrug resistance of cancer by double-targeting folate receptor and early endosomal pH

An optimized, pH-sensitive mixed-micelle system conjugated with folic acid is prepared in order to challenge multidrug resistance (MDR) in cancers. The micelles are composed of poly(histidine (His)-co-phenylalanine (Phe))-b-poly(ethylene glycol) (PEG) and poly(L-lactic acid) (PLLA)-b-PEG-folate. Core-forming, pH-sensitive hydrophobic blocks of poly(His-co-Phe) of varying composition are synthesized. The pH sensitivity of the micelles is controlled by the copolymer composition and is fine tuned to early endosomal pH by blending PLLA(3K)-b-PEG(2K)-folate in the presence of a basic anticancer drug, doxorubicin (DOX). In vitro tests are conducted against both wild-type (A2780) and DOX-resistant ovarian carcinoma cell lines. A mixed-micelle system composed of poly(His-co-Phe (16 mole%))-b-PEG (80 wt%) and PLLA-b-PEG-folate (20 wt%) is selected to target early endosomal pH. DOX-loaded micelles effectively kill both wild-type sensitive (A2780) and DOX-resistant ovarian MDR cancer-cell lines (A2780/DOX(R)) through an instantaneous high dose of DOX in the cytosol, which results from active internalization, accelerated DOX release triggered by endosomal pH, and an endosomal membrance disruption.     

Core/shell nanoparticles for pH-sensitive delivery of doxorubicin

Core/shell nanoparticles with lipid core were prepared and characterized as pH-sensitive delivery system of anticancer drug. The lipid core is composed of drug-loaded lecithin and the polymeric shell is composed of Pluronics (poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) tri-block copolymer, F-127). Based on the preparation method in the previous report by us, the freeze-drying of drug-loaded lecithin was performed in the F-127 aqueous solution containing trehalose used as a cryoprotectant to form stabilized core/shell nanoparticles. For the application of core/shell nanoparticles as a pH-sensitive drug delivery system for anticancer drug, doxorubicin was loaded into the core/shell nanoparticles and the drug loading amount and drug release behavior in response to pH change were observed.     

Dual-pH-sensitive mesoporous silica nanoparticle-based drug delivery system for tumor-triggered intracellular drug release

Reducing the side effects and improving the drug utilization are important work in anti-cancer drug delivery. In this paper, a novel dual-pH-sensitive drug delivery system was reported. Mesoporous silica nanoparticle (MSN) was applied to load anti-cancer drug doxorubicin hydrochloride (DOX) and was covered by mono-6-deoxy-6-EDA-β-cyclodextrine (β-CD-NH₂) to block the pores through pH-sensitive boronate ester bond. And the carriers were then coated with methoxy poly(ethylene glycol) (mPEG) through another pH-sensitive benzoic imine bond. mPEG leaving studies, in vitro cellular uptake studies and the flow cytometry analysis, proved that carriers was “stealthy” at pH 7.4, but could be “activated” for cytophagy by cancer cells in weakly acidic tumor tissues (pH 6.5) due to the departure of mPEG. β-CD-NH₂ leaving studies, the in vitro drug release studies and the in vitro cytotoxicity studies proved that boronate ester bond linking MSN and β-CD-NH₂ was stable at both pH 7.4 and 6.5, but could be hydrolyzed intracellular to release DOX for cellular apoptosis due to the lower pH (5.0). In summary, the novel dual-pH-sensitive drug delivery system fabricated with a dynamic protection strategy should have great application potential in anti-cancer drug delivery fields.     

A pH-sensitive theranostics system based on doxorubicin conjugated with the comb-shaped polymer coating of quantum dots

A two-phase route was developed to form a new theranostics-based system. The comb polymer poly (glycidyl methacrylate)-graft-ethane diamine-graft-polyethylene glycol (PGMA-g-EDA-g-PEG) was used to modify the quantum dots (QDs) by the method of ligand exchange. Subsequently, due to a large amount of amino groups on the surface of QDs, the doxorubicin (DOX) was conjugated by amine bonds to form pH-sensitive drug release system. UV–vis transmission spectra and PL spectra showed that the nanoparticles maintained the optical properties of QDs and DOX. The transmission electron microscopy analysis indicated that QDs were well dispersed in water and still had small sizes (7 nm) after ligand exchange and conjugated with DOX. Then the thermogravimetric analysis (TGA) revealed that about 80 wt% comb-shaped polymers coated on the surface of QDs, and about 10 wt% QDs was in nanoparticles PGMA-g-EDA-g-PEG-QDs-DOX. In vitro release studies showed that PGMA-g-EDA-g-PEG -DOX and PGMA-g-EDA-g-PEG-QDs-DOX were pH sensitive. Findings from this study suggested that nanoparticles PGMA-g-EDA-g-PEG-QDs-DOX can be used in a new field combined both imaging and targeted therapy.     

Influence of ibuprofen addition on the properties of a bioactive bone cement

Bioactive bone cements can promote bone growth and the formation of a strong chemical bond between the implant and bone tissue increasing the lifetime of the prosthesis. This study aims at synthesizing a new bioactive bone cement with different amounts of ibuprofen (5, 10 and 20 wt%) using a low toxicity activator, and investigating its in vitro release profile. The effect of ibuprofen (IB) on the setting parameters, residual monomer and bioactivity in synthetic plasma was also evaluated. It was verified that the different IB contents do not prevent the growth of calcium phosphate aggregates on composite surfaces, confirming that the cements are potentially bioactive. A relevant advantage of these formulations was a significant improvement in their curing parameters with increasing IB amount, associated to a reduction of the peak temperature and an extension of the setting time. The investigated cements released an average of about 20 % of the total incorporated ibuprofen during 30 days test, with IB20 liberating the highest percentage of drug 20.6 %, and IB10 and IB5, respectively 19.1 and 17.6 %. This behavior was attributed to the low solubility of this drug in aqueous media and was also related with the hydrophobic character of the polymer. Regarding the therapeutic concentration sufficient to suppress inflammation, the cement with 10 % of ibuprofen achieved the required release rate for 1 week and the cement with 20 % for 2 weeks.     

Preparation and characterization of magnetic alginate-chitosan hydrogel beads loaded matrine

The aim of this study was to use alginate-chitosan (Alg-CS) hydrogel beads for developing an oral water-soluble drug delivery system, occupying pH-sensitive property and superparamagnetic. Matrine as a model drug was loaded in Alg-CS hydrogel beads to study the release character of the delivery system. The amount of matrine released from the beads was relatively low in pH 2.5 over 8?h (34.90%), but nearly all of the initial drug content was released in simulated intestinal fluid (SIF, pH 6.8) within 8?h. The results demonstrated that Alg-CS hydrogel beads possess unique pH-dependent swelling behaviors. In addition, the magnetic beads were characterized by Fourier transform infrared spectroscopy, scanning electron microscope, X-ray diffractometry and vibrating-sample magnetometry. Magnetometer measurements data suggested that Alg-CS beads also had superparamagnetic property as well as fast magnetic response. It can be expected that the beads can deliver and release encapsulated anticancer agent at the tumor by the weak magnetic field, and hence could be potential candidates as an orally administered drug delivery system.     

Preparation and characterization of magnetic alginate-chitosan hydrogel beads loaded matrine

The aim of this study was to use alginate-chitosan (Alg-CS) hydrogel beads for developing an oral water-soluble drug delivery system, occupying pH-sensitive property and superparamagnetic. Matrine as a model drug was loaded in Alg-CS hydrogel beads to study the release character of the delivery system. The amount of matrine released from the beads was relatively low in pH 2.5 over 8?h (34.90%), but nearly all of the initial drug content was released in simulated intestinal fluid (SIF, pH 6.8) within 8?h. The results demonstrated that Alg-CS hydrogel beads possess unique pH-dependent swelling behaviors. In addition, the magnetic beads were characterized by Fourier transform infrared spectroscopy, scanning electron microscope, X-ray diffractometry and vibrating-sample magnetometry. Magnetometer measurements data suggested that Alg-CS beads also had superparamagnetic property as well as fast magnetic response. It can be expected that the beads can deliver and release encapsulated anticancer agent at the tumor by the weak magnetic field, and hence could be potential candidates as an orally administered drug delivery system.     

以电纺丝蛋白纤维为模板的pH响应性介孔SiO2纳米管的制备及药物释放

以资源丰富的家蚕丝为原料,氯化钙/甲酸为溶解体系,利用静电纺丝法制得丝素蛋白（SF）纳米纤维;以SF纤维为模板在其表面涂覆SiO₂,经煅烧后获得了介孔SiO₂纳米管（MSNTs）;在MSNTs管壁上接枝醛基（-CHO）,利用醛基与盐酸阿霉素（DOXHCl）氨基之间的动态共价键制得了pH响应性药物释放体系。通过SEM、TEM、TG、比表面积（BET）分析、FTIR及紫外-可见吸收（UV-Vis）光谱对MSNTs的微观结构、功能化及载药体系的pH响应性进行了表征。结果表明:当SF浓度在15wt%~17wt%时,可获得圆柱状且直径在（113±27）~（134±32）nm范围内可调的SF纤维模板;通过调整涂覆液中十六烷基三甲基溴化铵（CTAB）的浓度来调节MSNTs管壁的厚度,当CTAB用量从1.25 mg/mL增加到3.75 mg/mL时,MSNTs管壁厚度从30~39 nm增加到63~65 nm,对应的比表面积从154 m2/g下降到98 m2/g,介孔平均孔径从12.5 nm下降到10.0 nm;醛基修饰的MSNTs载DOXHCl（MSNT-CHO-DOX）体系,在pH值分别为7.4、6.5和5.5的磷酸氢二钾-磷酸二氢钾（PB）缓冲溶液中进行释放,100 h时释药率分别达到23%、35%和75%,实现了MSNT-CHO-DOX载药体系的pH响应性释放。      

PSY-g-PAA/APT/SA载药复合凝胶小球的制备及释药性能

采用离子凝胶法制备了欧车前胶-g-聚丙烯酸/凹凸棒黏土/海藻酸钠(PSY-g-PAA/APT/SA)载药复合凝胶小球,以双氯芬酸钠为模型药物,考察了pH敏感性和凹凸棒黏土含量对凝胶小球的包封率、载药率、溶胀性能和药物释放行为的影响。结果表明,当释放介质为模拟胃液(pH=1.2)时,药物基本不释放;而为模拟肠液(pH=6.8)时,5h后累积释放率超过90%,复合凝胶小球具有明显的pH敏感性。随着凝胶小球中凹凸棒黏土含量的增加,溶胀率和药物累积释放率均减小,表明凹凸棒黏土的引入可以减缓药物的突释效应。     

A pH-switched mesoporous nanoreactor for synergetic therapy

Zinc oxide nanoparticles (ZnO NPs),as a new type of pH-sensitive drug carrier,have received much attention.ZnO NPs are stable at physiological pH,but can dissolve quickly in the acidic tumor environment (pH ＜ 6) to generate cytotoxic zinc ions and reactive oxygen species (ROS).However,the protein corona usually causes the non-specific degradation of ZnO NPs,which has limited their application considerably.Herein,a new type of pH-sensitive nanoreactor (ZnO-DOX@F-mSiO2-FA),aimed at reducing the non-specific degradation of ZnO NPs,is presented.In the acidic tumor environment (pH ＜ 6),it can release cytotoxic zinc ions,ROS,and anticancer drugs to kill cancer cells effectively.In addition,the fluorescence emitted from fluorescein isothiocyanate (FITC)-labeled mesoporous silica (F-mSiO2) and doxorubicin (DOX) can be used to monitor the release behavior of the anticancer drug.This report provides a new method to avoid the non-specific degradation of ZnO NPs,resulting in synergetic therapy by taking advantage of ZnO NPs-induced oxidative stress and targeted drug release.     

The grafting and release behavior of doxorubincin from Fe(3)O(4)@SiO(2) core-shell structure nanoparticles via an acid cleaving amide bond: the potential for magnetic targeting drug delivery

Fe(3)O(4)@SiO(2) core-shell structure nanoparticles were first prepared and characterized by TEM, FTIR, XPS and XRD. Subsequently the widely used anticancer agent doxorubincin (DOX) was successfully grafted to the surface of the core-shell nanoparticles via an amide bond with the aid of a spacer arm we synthesized. The spacer arm met two needs: one end can couple to the core-shell nanoparticles' surface while the other end was the active?-COOH group, which can react with the?-NH(2) group of DOX molecules. The synthesized spacer arm and the conjugation of the drug with nanoparticles through amidation were confirmed by FTIR. The DOX-loading efficiency determined by UV-vis spectrometer was 86.5%. Drug release experiments displayed a pH-dependent behavior that DOX was cleaved from the nanoparticles easily under low pH conditions in the presence of protease and that most of the conjugated doxorubincin were released within the first 12?h. The prepared DOX-grafted Fe(3)O(4)@SiO(2) core-shell structure nanoparticles showed a superparamagnetic property with a saturation magnetization value of 49.3?emu?g(-1), indicating a great potential application in the treatment of cancer using magnetic targeting drug-delivery technology.     

Influence of strontium for calcium substitution in bioactive glasses on degradation,ion release and apatite formation

Bioactive glasses are able to bond to bone through the formation of hydroxy-carbonate apatite in body fluids while strontium (Sr)-releasing bioactive glasses are of interest for patients suffering from osteoporosis, as Sr was shown to increase bone formation both in vitro and in vivo. A melt-derived glass series (SiO₂–P₂O₅–CaO–Na₂O) with 0–100% of calcium (Ca) replaced by Sr on a molar base was prepared. pH change, ion release and apatite formation during immersion of glass powder in simulated body fluid and Tris buffer at 37°C over up to 8 h were investigated and showed that substituting Sr for Ca increased glass dissolution and ion release, an effect owing to an expansion of the glass network caused by the larger ionic radius of Sr ions compared with Ca. Sr release increased linearly with Sr substitution, and apatite formation was enhanced significantly in the fully Sr-substituted glass, which allowed for enhanced osteoblast attachment as well as proliferation and control of osteoblast and osteoclast activity as shown previously. Studying the composition–structure–property relationship in bioactive glasses enables us to successfully design next-generation biomaterials that combine the bone regenerative properties of bioactive glasses with the release of therapeutically active Sr ions.     

Dual-controlled oral colon-targeted delivery of bovine insulin based on mesoporous phosphonate

The time- and pH-controlled oral colon-targeted delivery system for bovine insulin was developed by dip-coating lag-time films on tablet comprising bovine insulin-loaded pH-sensitive mesoporous phosphonate (ZrBPMP-3) as tablet core and absorption enhancer of insulin, sodium glycocholate, in outer layer, in which the lag time can be controlled via adjusting coating times of lag-time films and the release of bovine insulin in the colon can be triggered by pH-sensitive ZrBPMP-3. The pH transition release experiments show that the tablet with four times lag-time films coating can carry bovine insulin passing through the stomach and small intestine with a minimum release and trigger off the release of loaded bovine insulin in the colon under dual control, time control and pH value control. Furthermore, the released bovine insulin can still retain its native conformation, as evidenced by circular dichroism spectroscopy, indicating that bovine insulin cannot denature and lose its bioactive conformation during the loading, lag-time films coating, delivery and release. In addition, it is worth mentioning that ZrBPMP-3 almost exhibits non-cytotoxicity at low concentration in MTT assays. Thus, ZrBPMP-3 as a new kind of carrier and based on which developing controllable colon-targeted delivery system have potential application in oral delivery of insulin and even other therapeutic peptides and proteins.     

pH-Controlled drug release from mesoporous silica tablets coated with hydroxypropyl methylcellulose phthalate

A simple pH-controlled drug release system was successfully prepared by coating pH-sensitive polymer hydroxypropyl methylcellulose phthalate (HPMCP) on drug-loaded mesoporous SBA-15 tablet. Using famotidine (Famo) as a model drug, the effects of coating times and drying temperature on drug release were studied in detail to optimize the drug release system. In simulated gastric fluid (SGF, pH 1.2), it took only 2 h for Famo to be completely released from mesoporous silica tablet without HPMCP coating. Also in SGF, with the increase of coating times and drying temperature, the release of Famo was greatly delayed by HPMCP coating. For the tablet with twice coating of HPMCP and dried at 80 °C, only 4.0 wt.% of Famo could be released within 4 h. However, in simulated intestinal fluid (SIF, pH 7.4), HPMCP coating did not show obvious effect on the release of Famo.     

In vitro evaluation of folic acid modified carboxymethyl chitosan nanoparticles loaded with doxorubicin for targeted delivery

The development of smart targeted nanoparticle that can deliver drugs to direct cancer cells, introduces better efficacy and lower toxicity for treatment. We report the development and characterizations of pH-sensitive carboxymethyl chitosan modified folic acid nanoparticles and manifest their feasibility as an effective targeted drug delivery vehicle. The nanoparticles have been synthesized from carboxymethyl chitosan with covalently bonded bifunctional 2,2′-(ethylenedioxy)-bis-(ethylamine) (EDBE) through the conjugation with folic acid. The conjugation has been analyzed by Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy. The resultant nanoparticles with an average size less then 200 nm measured by dynamic light scattering and transmission electron microscopy. Confocal microscopy and flow cytometric analysis have revealed that folate-mediated targeting significantly enhances the cellular uptake of the nanoparticle and thus facilitates apoptosis of cancer cells (HeLa, B16F1). For the application of the nanoparticles as a drug carrier, Doxorubicin a potent anticancer drug has been loaded into the nanoparticles, with the drug loading amount and the drug release pattern observed.     

Rapid Light‐Triggered Drug Release in Liposomes Containing Small Amounts of Unsaturated and Porphyrin–Phospholipids

Prompt membrane permeabilization is a requisite for liposomes designed for local stimuli‐induced intravascular release of therapeutic payloads. Incorporation of a small amount (i.e., 5 molar percent) of an unsaturated phospholipid, such as dioleoylphosphatidylcholine (DOPC), accelerates near infrared (NIR) light‐triggered doxorubicin release in porphyrin–phospholipid (PoP) liposomes by an order of magnitude. In physiological conditions in vitro, the loaded drug can be released in a minute under NIR irradiation, while liposomes maintain serum stability otherwise. This enables rapid laser‐induced drug release using remarkably low amounts of PoP (i.e., 0.3 molar percent). Light‐triggered drug release occurs concomitantly with DOPC and cholesterol oxidation, as detected by mass spectrometry. In the presence of an oxygen scavenger or an antioxidant, light‐triggered drug release is inhibited, suggesting that the mechanism is related to singlet oxygen mediated oxidization of unsaturated lipids. Despite the irreversible modification of lipid composition, DOPC‐containing PoP liposome permeabilization is transient. Human pancreatic xenograft growth in mice is significantly delayed with a single chemophototherapy treatment following intravenous administration of 6 mg kg^?1 doxorubicin, loaded in liposomes containing small amounts of DOPC and PoP.     

Bioactive silica-based nanomaterials for doxorubicin delivery: Evaluation of structural properties associated with release rate

This study investigated the use of a novel particle-type formulation, composed of a sol–gel derived bioactive silica-poly(dimethylsiloxane) composite containing calcium and phosphate, as a slow release delivery system for an anticancer drug (doxorubicin hydrochloride, DOX). DOX in the solution form was in situ incorporated into the composite network during the sol–gel process. The DOX loaded-formulation was immersed in a simulated body fluid (SBF) having ion concentrations and a pH value nearly equal to those of human blood plasma. The effect of different drug loads and particle sizes — on the release profiles in such biomimetic conditions was studied. The bioactivity was examined in vitro with respect to the ability of hydroxyapatite layer to form on the surface of residual DOX-loaded formulation as a result of contact with SBF. The infrared absorption spectra, scanning electron microscopy, nitrogen gas adsorption/desorption, and X-ray powder diffraction studies were conducted before and after contact of the formulation with SBF. The results show that all the DOX-loaded formulations are characterized by mesoporosity with the uniform pore-size-distribution. The release profiles of DOX consisted of two sequential zero order-controlled stages with distinctly different release rates. After 20 days of DOX release, a semicrystalline carbonated hydroxyapatite with a highly developed porous structure was formed, indicative of their bioactive character. Furthermore, these new covered-particle-type formulations released DOX over 1 month at a constant rate.     

硼酸盐玻璃的原位转化及对浸泡液酸碱度的影响

采用火焰喷球法制备了组成为10Na₂O-10CaO-80B₂O₃(wt%)和19Na₂O-17CaO-64B₂O₃(wt%)的钠钙硼(NCB)玻璃(分别记为S1和S2)微球, 通过pH计、XRD、SEM、SEM-EDS、FTIR和BET研究了两种微球原位转化为中空羟基磷灰石(HA)微球及对浸泡液酸碱度的影响, 并以万古霉素为模型药物, 进一步研究了中空HA微球的缓释性能。结果表明, S1-HA微球具有较大的空腔体积和较好的药物负载性能, 其载药量和载药率分别达到13.5 mg/g和16.8%; 而S2微球对浸泡液pH的影响相对较强, S2-HA微球呈现显著的层状结构, 且具有较好的缓释性能, 其缓释时间可达到60 h。     

Loading and Release Mechanism of Red Clover Necrotic Mosaic Virus Derived Plant Viral Nanoparticles for Drug Delivery of Doxorubicin

Loading and release mechanisms of Red clover necrotic mosaicvirus (RCNMV) derived plant viral nanoparticle (PVN) are shown for controlled delivery of the anticancer drug, doxorubicin (Dox). Previous studies demonstrate that RCNMV's structure and unique response to divalent cation depletion and re‐addition enables Dox infusion to the viral capsid through a pore formation mechanism. However, by controlling the net charge of RCNMV outer surface and accessibility of RCNMV interior cavity, tunable release of PVN is possible via manipulation of the Dox loading capacity and binding locations (external surface‐binding or internal capsid‐encapsulation) with the RCNMV capsid. Bimodal release kinetics is achieved via a rapid release of surface‐Dox followed by a slow release of encapsulated Dox. Moreover, the rate of Dox release and the amount of released Dox increases with an increase in environmental pH or a decrease in concentration of divalent cations. This pH‐responsive Dox release from PVN is controlled by Fickian diffusion kinetics where the release rate is dependent on the location of the bound or loaded active molecule. In summary, controllable release of Dox‐loaded PVNs is imparted by 1) formulation conditions and 2) driven by the capsid's pH‐ and ion‐ responsive functions in a given environment.