Calcium phosphate/block copolymer hybrid porous nanospheres: Preparation and application in drug delivery

Calcium phosphate (CaP)/block copolymer hybrid porous nanospheres were synthesized by a simple solution method using CaCl₂ and (NH₄)₂HPO₄ in the presence of a block copolymer at room temperature. X-ray diffraction showed that the sample consisted of amorphous calcium phosphate (ACP). The BET specific surface area and the pore size distribution of the CaP/PLLA-mPEG hybrid porous nanospheres were also characterized. The as-prepared CaP/PLLA-mPEG hybrid porous nanospheres were explored as drug carriers, and showed a high ibuprofen loading capacity and in vitro prolonged drug release behavior in a simulated body fluid. These CaP/block copolymer hybrid porous nanospheres exhibit a great potential for application in drug delivery.     

β-TCP porous pellets as an orthopaedic drug delivery system: ibuprofen/carrier physicochemical interactions

Calcium phosphate bone substitute materials can be loaded with active substances for in situ, targeted drug administration. In this study, porous β-TCP pellets were investigated as an anti-inflammatory drug carrier. Porous β-TCP pellets were impregnated with an ethanolic solution of ibuprofen. The effects of contact time and concentration of ibuprofen solution on drug adsorption were studied. The ibuprofen adsorption equilibrium time was found to be one hour. The adsorption isotherms fitted to the Freundlich model, suggesting that the interaction between ibuprofen and β-TCP is weak. The physicochemical characterizations of loaded pellets confirmed that the reversible physisorption of ibuprofen on β-TCP pellets is due to Van der Waals forces, and this property was associated with the 100% ibuprofen release.     

β-TCP porous pellets as an orthopaedic drug delivery system: ibuprofen/carrier physicochemical interactions

Abstract

Calcium phosphate bone substitute materials can be loaded with active substances for in situ, targeted drug administration. In this study, porous β-TCP pellets were investigated as an anti-inflammatory drug carrier. Porous β-TCP pellets were impregnated with an ethanolic solution of ibuprofen. The effects of contact time and concentration of ibuprofen solution on drug adsorption were studied. The ibuprofen adsorption equilibrium time was found to be one hour. The adsorption isotherms fitted to the Freundlich model, suggesting that the interaction between ibuprofen and β-TCP is weak. The physicochemical characterizations of loaded pellets confirmed that the reversible physisorption of ibuprofen on β-TCP pellets is due to Van der Waals forces, and this property was associated with the 100% ibuprofen release.     

TiO_2/SiO_2复合中空微球的选择性改性与药物缓释性能研究

以聚合物微球为模板,通过溶胶-凝胶法制备了TiO2/SiO2复合中空微球,并分别采用硬脂酸和无机磷酸对内层二氧化钛进行了疏水和亲水改性.扫描电镜(SEM)和氮气吸附-脱附结果表明中空微球具有完整的球形空腔和多孔的壳层孔道结构.傅立叶红外光谱(FTIR)证实了内部疏水及亲水改性层的存在.以布洛芬药物为对象,采用热重分析(TGA)和高效液相色谱(HPLC)考察了不同改性对复合中空微球的载药量及缓释性能的影响.研究结果表明,由于存在疏水作用,硬脂酸改性的中空微球载药量(189.8mg/g)高于未改性中空微球(177.5mg/g),且药物释放速率明显减慢,53h内药物释放率仅为55%;与此相反,无机磷酸亲水改性的中空微球载药量减小(为153.0mg/g),且释放速率提高,10h内释放了将近80%的药物.因此,采用不同的改性基团可以对复合中空微球的药物释放速率进行有效地调控.     

Release of PLGA–encapsulated dexamethasone from microsphere loaded porous surfaces

The aim of the present study was to investigate the morphology and function of a drug eluting metallic porous surface produced by the immobilization of poly lactide-co-glycolide microspheres bearing dexamethasone onto plasma electrolytically oxidized Ti–6Al–7Nb medical alloy. Spheres of 20 μm diameter were produced by an oil-in-water emulsion/solvent evaporation method and thermally immobilized onto titanium discs. The scanning electron microscopy investigations revealed that the size distribution and morphology of the attached spheres had not changed significantly. The drug release profiles following degradation in phosphate buffered saline for 1000 h showed that, upon immobilisation, the spheres maintained a sustained release, with a triphasic profile similar to the non-attached system. The only significant change was an increased release rate during the first 100 h. This difference was attributed to the effect of thermal attachment of the spheres to the surface.     

Size effect of PLGA spheres on drug loading efficiency and release profiles

Drug delivery systems (DDS) based on poly (lactide-co-glycolide) (PLGA) microspheres and nanospheres have been separately studied in previous works as a means of delivering bioactive compounds over an extended period of time. In the present study, two DDS having different sizes of the PLGA spheres were compared in morphology, drug (dexamethasone) loading efficiency and drug release kinetics in order to investigate their feasibility with regard to production of medical combination devices for orthopedic applications. The loaded PLGA spheres have been produced by the oil-in-water emulsion/solvent evaporation method following two different schemes. Their morphology was assessed by scanning electron microscopy and the drug release was monitored in phosphate buffer saline solution at 37°C for 550 h using high performance liquid chromatography. The synthesis schemes used produced spheres with two different and reproducible size ranges (20 ± 10 and 1.0 ± 0.4 μm) having a smooth outer surface and regular shape. The drug loading efficiency of the 1.0 μm spheres was found to be 11% as compared to just 1% for the 20 μm spheres. Over the 550 h release period, the larger spheres (diameter 20 ± 10 μm) released 90% of the encapsulated dexamethasone in an approximately linear fashion whilst the relatively small spheres (diameter 1.0 ± 0.4 μm) released only 30% of the initially loaded dexamethasone, from which 20% within the first 25 h. The changes observed were mainly attributed to the difference in surface area between the two types of spheres as the surface texture of both systems was visibly similar. As the surface area per unit volume increases in the synthesis mixture, as is the case for the 1.0 μm spheres formulation, the amount of polymer-water interfaces increases allowing more dexamethasone to be encapsulated by the emerging polymer spheres. Similarly, during the release phase, as the surface area per unit volume increases, the rate of inclusion of water into the polymer increases, permitting faster diffusion of dexamethasone.     

Calcium carbonate microspheres as carriers for the anticancer drug camptothecin

Biogenic calcium carbonate has come to the attention of many researchers as a promising drug delivery system due to its safety, pH sensitivity and the large volume of information already in existence on its medical use. In this study, we employed bovine serum albumin (BSA) as an additive to synthesize a series of porous calcium carbonate microspheres (CCMS). These spheres, identified as vaterite, are stable both in aqueous solutions and organic solvents. Camptothecin, an effective anticancer agent, was loaded into the CCMS by simple diffusion and adsorption. The camptothecin loaded CCMS showed sustained cell growth inhibitory activity and a pH dependent release of camptothecin. With a few hours, the release is negligible under physiological conditions (pH = 7.4) but almost complete at pH 4 to 6 (i.e. pHs found in lysosomes and solid tumor tissue respectively). These findings suggest that porous, biogenic calcium carbonate microspheres could be promising carriers for the safe and efficient delivery of anticancer drugs of low aqueous solubility.     

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.     

Facile one-pot synthesis and drug storage/release properties of hollow micro/mesoporous organosilica nanospheres

Novel hollow micro/mesoporous organosilica nanospheres (HMOSNs) of uniform diameter and shell thickness of about 90 nm and 15 nm, respectively, and with wormlike micro/mesoporous shell full of uramido groups, have been successfully fabricated by a facile one-pot route. The micro/mesoporosity of the synthesized HMOSNs has been characterized by small-angle and wide-angle X-ray diffraction (XRD), scan electron microscopy (SEM), transmission electron microscopy (TEM) and nitrogen adsorption-desorption measurements. The drug storage and release properties of the synthetic HMOSNs are measured by using ibuprofen (IBU) as a model drug, and a high drug storage capacity of 531 mg IBU per gram HMOSNs and a steady drug release behavior are exhibited.     

An asymmetric coating composed of gelatin and hydroxyapatite for the delivery of water insoluble drug

An asymmetric coating composed of gelatin and hydroxyapatite on Ti6Al4V alloy implant was prepared to control the release of water-insoluble drug ibuprofen and improve the surface properties of the implant. The asymmetric coating developed into a thin dense outer layer and a thick porous inner layer using a dip-coating method and a succedent phase-inversion process. The drug loading ranged from 10 to 30% (w/w), and depended on the immersion time and drug concentration in the quenching solution. The in vitro release from this system was always at an approximately zero-order rate and at least lasted for 30 days. The in vitro studies in SBF revealed that the coating could induce the formation of apatite, and was fully covered after 14 days soaking in SBF solution. This asymmetric coating had better bioactivity of inducing the formation of apatite in vitro, compared with pure gelatin coating and bare Ti6Al4V implant.     

Novel photothermal-responsive sandwich-structured mesoporous silica nanoparticles: synthesis,characterization, and application for controlled drug delivery

Novel thermal nanoparticles [hollow mesoporous silica nanospheres (HMSNs)–poly (N-isopropyl acrylamide-acrylic acid) PNIPAM-AA] were developed with Ag nanoparticles (AgNps) as the core, mesoporous silica nanoparticles as the layer, and thermally responsive polymers PNIPAM-AA as the shell. The AgNps had good photothermal effects, PNIPAM-AA was responsive to temperature, the combination of AgNps and PNIPAM-AA could be used as a photothermal-responsive switch for drug release, and HMSNs greatly increased the drug loading of the carrier. The samples were characterized by means of scanning electron microscopy, transmission electron microscopy, N₂ adsorption–desorption, thermogravimetric analysis, Fourier transform infrared spectroscopy, and UV–Vis absorption spectra. The results showed that Ag@HMSN nanoparticles possessed a uniform diameter (330 nm), high specific surface area (822.45 m²/g), and mesoporous pore size (2.75 nm). Using ibuprofen (IBU) as a model drug, the release process was monitored under in vitro conditions to investigate its release characteristics at different temperatures. The results showed that the nanoparticles had a significant regulatory effect on IBU release.

Graphical abstract

     

ATP‐Stabilized Amorphous Calcium Carbonate Nanospheres and Their Application in Protein Adsorption

Calcium carbonate is a common substance found in rocks worldwide, and is the main biomineral formed in shells of marine organisms and snails, pearls and eggshells. Amorphous calcium carbonate (ACC) is the least stable polymorph of calcium carbonate, which is so unstable under normal conditions that it is difficult to be prepared in vitro because it rapidly crystallizes to form one of the more stable polymorphs in aqueous solution. Herein, we report the successful synthesis of highly stable ACC nanospheres in vitro using adenosine 5′‐triphosphate disodium salt (ATP) as a stabilizer. The effect of ATP on the stability of ACC nanospheres is investigated. Our experiments show that ATP plays an unique role in the stabilization of ACC nanospheres in aqueous solution. Moreover, the as‐prepared ACC nanospheres are highly stable in phosphate buffered saline for a relatively long period of time (12 days) even under relatively high concentrations of calcium and phosphate ions. The cytotoxicity tests show that the as‐prepared highly stable ACC nanospheres have excellent biocompatibility. The highly stable ACC nanospheres have high protein adsorption capacity, implying that they are promising for applications in biomedical fields such as drug delivery and protein adsorption.     

Synthesis and release of trace elements from hollow and porous hydroxyapatite spheres

It is known that organic species regulate fabrication of hierarchical biological forms via solution methods. However, in this study, we observed that the presence of inorganic ions plays an important role in the formation and regulation of biological spherical hydroxyapatite formation. We present a mineralization method to prepare ion-doped hydroxyapatite spheres with a hierarchical structure that is free of organic surfactants and biological additives. Porous and hollow strontium-doped hydroxyapatite spheres were synthesized via controlling the concentration of strontium ions in a calcium and phosphate buffer solution. Similarly, fluoride and silicon-doped hydroxyapatite spheres were synthesized. While spherical particle formation was attainable at low and high temperature for Sr-doped hydroxyapatite, it was only possible at high temperature in the F/Si-doped system. The presence of inorganic ions not only plays an important role in the formation and regulation of biological spherical hydroxyapatite, but also could introduce pharmaceutical effects as a result of trace element release. Such ion release results showed a sustained release with pH responsive behavior, and significantly influenced the hydroxyapatite re-precipitation. These ion-doped hydroxyapatite spheres with hollow and porous structure could have promising applications as bone/tooth materials, drug delivery systems, and chromatography supports.     

Thermal stability of porous A-type carbonated hydroxyapatite spheres

Porous A-type carbonated hydroxyapatite (CHAp) spheres were synthesized in the high-pressure hydrothermal system by the template-directed method. The thermal stability of porous A-type CHAp spheres was first studied via calcining in the wide temperature range from 393 K up to 1173 K, analyzed by FT-IR, XRD and SEM. The results showed that the decomposition of porous A-type CHAp spheres went through two stages, owing to the release of the carbonate from the OH⁻ channel and the collapse of apatite-type structure above 973 K, consecutively. The nanoparticles in situ replaced the flakelets of porous CHAp spheres and packed closely into new regular porous Ca₃(PO₄)₂ spheres.     

Development of porous HAp and β-TCP scaffolds by starch consolidation with foaming method and drug-chitosan bilayered scaffold based drug delivery system

The inability to maintain high concentrations of antibiotic at the site of infection for an extended period of time along with dead space management is still the driving challenge in treatment of osteomyelitis. Porous bioactive ceramics such as hydroxyapatite (HAp) and beta-tri calcium phosphate (β-TCP) were some of the alternatives to be used as local drug delivery system. However, high porosity and high interconnectivity of pores in the scaffolds play a pivotal role in the drug release and bone resorption. Ceftriaxone is a cephalosporin that has lost its clinical popularity. But has recently been reported to exhibit better bactericidal activity in vitro and reduced probability of resistance development, in combination with sulbactam, a β-lactamase inhibitor. In this article, a novel approach of forming HAp and pure β-TCP based porous scaffolds by applying together starch consolidation with foaming method was used. For the purpose, pure HAp and β-TCP were prepared in the laboratory and after thorough characterization (including XRD, FTIR, particle size distribution, etc.) the powders were used for scaffold fabrication. The ability of these scaffolds to release drugs suitably for osteomyelitis was studied in vitro. The results of the study indicated that HAp exhibited better drug release profile than β-TCP when drug was used alone indicating the high influence of the carrier material. However, this restriction got relaxed when a bilayered scaffold was formed using chitosan along with the drug. SEM studies along with EDAX on the drug-chitosan bilayered scaffold showed closest apposition of this combination to the calcium phosphate surface.     

Targeted drug delivery using silica xerogel systems to treat diseases due to intracellular pathogens

Intracellular bacterial pathogens like Salmonella, Brucella, Mycobacterium and Listeria have developed various mechanisms to invade host cells, and they can establish persistent infections. Treatment and eradication are difficult in vivo due to its localization at the cellular level and many of the available antimicrobials cannot efficiently penetrate cell membrane. Development of a method to effectively deliver the drug in to phagocytic cells is the use of carrier system that will encapsulate the drug, transport them to the target cell and release the drugs within the cells where they can reach the intracellular bacteria. The recently developed sol–gel technique offers new possibilities for embedding organic compounds within a porous silica matrix and for controlling their release from the host matrix into a surrounding medium. We investigated a sol–gel derived silica xerogel as a delivery system for the prolonged release of gentamicin for treatment of Salmonella infection in a mouse model. The particle sizes of our porous silica are in a broad range from 1.7 to 3.3 µm. The release of gentamicin from the inside hollow part of the porous carrier can last a comparatively long time, leading to a delayed release of the drug (90% of gentamicin released in 5 days). Administration of three doses of porous silica loaded with gentamicin reduced the CFU of S. thyphimurium in livers of infected mice by 0.48 log compared to 0.13  log with free drug. This new approach, utilizing sol–gel carrier systems for drug delivery, should improve our capability for targeting intracellular pathogens.     

中空层状羟基磷灰石微球对溶菌酶的吸附与缓释研究

利用锂钙硼玻璃在磷酸盐溶液中的原位转化反应制备表面多孔且具有中空层状结构的羟基磷灰石(HA)微球,以溶菌酶为蛋白的药物模型,研究了中空层状结构的羟基磷灰石微球对溶菌酶的吸附及缓释特性,结果显示,中空微球对不同浓度的溶菌酶溶液,具有不同的吸附机理,当溶菌酶溶液的浓度低于0.8mg/mL时,溶菌酶的吸附主要发生在微球的外表面,符合Langmuir模型,释放速率较快,48h内基本释放完全;当溶菌酶溶液的浓度高于0.8mg/mL时,溶菌酶扩散进入微球内部及球壁的微孔中,使得吸附量显著增加,满足Henry吸附模型,溶菌酶的释放周期明显增加,可持续释放800h,微球对蛋白具有很好的缓释效果。     

Biomimetic synthesis of the composites of hydroxyapatite and chitosan–phosphorylated chitosan polyelectrolyte complex

A polyelectrolyte complex (PEC) composed of chitosan (CS) and phosphorylated chitosan (PCS) was used to encapsulate a calcium phosphate by a biomimetic method. An acidic CS (polycation) solution containing calcium and phosphate ions (Ca²⁺: 6 mM, Ca/P = 1.67) was added into a PCS (polyanion) solution leading to the formation of a polyelectrolyte complex (PEC) with nanoscopic carbonate-containing, low-crystallinity hydroxyapatite (HA) distributed evenly in the fibrils of the PEC by controlled crystal growth. The resulting composite material, PEC–HA, has a complicated porous structure that is expected to have high biocompatibility and that may be of use as materials for bone replacement and a carrier for controlled-release therapeutic agents.     

Porous bioceramic bead prepared by calcium phosphate with sodium alginate gel and PE powder

The porous calcium phosphate beads were made by an alginate-interacting Ca ions mechanism on addition of a pore-forming polyethylene (PE) powder at 1250 °C sintering. The nature of the powders and porous beads were analyzed through X-ray diffraction (XRD), Fourier transform infrared spectrometry (FTIR) and heavy metal analysis by inductively coupled plasma-optical emission spectroscopy (ICP-OES). The porous beads size and the pore microstructure characteristics were determined using scanning electron microscopy (SEM). Beside, the porosity analysis was evaluated out using an Archimedes' principle and mercury porosimetry. Then, the sodium ampicillin was penetrated/adsorbed onto calcium-deficient hydroxyapatite porous beads, and was subsequently released in PBS. No matter whether the raw material was HAp, TCP or biphase, the Ca₉(HPO₄)(PO₄)₅OH phase (CDHA) was formed only after sintering. Porous beads of various calcium phosphates with different sizes (0.9–1.1 mm) and pore size groups (60–120 μm and lower than 10 μm) were appeared. The release kinetics of sodium ampicillin from these porous beads have indicated the possibility of using these materials as possible carriers for drug delivery.     

Porous calcium phosphate ceramics modified with PLGA–bioactive glass

Porous calcium phosphate ceramics (mainly hydroxyapatite) with interconnected macropores (∼1 mm) and micropores (∼5 μm) as well as high porosities (∼80%) were prepared by firing polyurethane foams that were coated with calcium phosphate cement at 1200 °C. In order to improve the mechanical properties such as compressive strength and compressive modulus and maintain the desirable bioactivity (i.e. the ability of apatite layer formation), the open micropores of the struts were infiltrated with poly(lactic-co-glycolic acid) (PLGA) to achieve an interpenetrating bioactive ceramic/biodegradable polymer composite structure. The PLGA filled struts were further coated with a 58S bioactive glass (33 wt.%)–PLGA composite coating. The PLGA–bioactive glass modified porous calcium phosphate ceramics proved to be bioactive and exhibited compressive strengths up to 7.7 MPa and compressive moduli up to 3 GPa, which were comparable to those of natural spongy bones. The obtained complex porous bioactive/biodegradable composites could be used as tissue engineering scaffolds for low-load bearing applications.