Sustained Drug Release Properties Research Articles

Facile one-pot synthesis of hollow mesoporous fluorescent Gd2O3:Eu/calcium phosphate nanospheres for simultaneous dual-modal imaging and pH-responsive drug delivery

The hollow nanospheres (NSs) composed of lanthanides have become a hot topic owing to their uncommon magnetic and optical properties arising from the 4f electrons. However, only a few novel methods have been developed for effectively integrating small calcium phosphate (CaP) nanoparticles and rare earth oxide drug carriers into an individual hollow mesoporous nanosphere. Herein, we report a facile, reproducible, room-temperature solution method to prepare multifunctional fluorescent hollow mesoporous Gd2O3:Eu/CaP (designated as HM-Gd2O3:Eu/CaP) NSs by using polyacrylic acid calcium (PAA-Ca) as a template. The excellent luminescent property and obvious T1-enhancement effect as well as the HM structure endow the HM-Gd2O3:Eu/CaP NSs with the capacity of simultaneous dual-modal fluorescence, magnetic resonance (MR) imaging and drug delivery. The nanocontainer-functionality of the HM-Gd2O3:Eu/CaP NSs is further validated upon filling with the anti-cancerogenic agent doxorubicin (drug-loading capacity is 749 μg mg−1). In addition, the HM-Gd2O3:Eu/CaP NSs display excellent pH-responsive and sustained drug release property. In vitro cell cytotoxicity tests verify the HM-Gd2O3:Eu/CaP NSs have good biocompatibility when the concentration ≤25 mg mL−1. Taken together, the results suggested that the HM-Gd2O3:Eu/CaP NSs can be applied as fluorescence and MR dual-modal imaging contrast agents and drug delivery vehicles.

Amino-functionalized poloxamer 407 with both mucoadhesive and thermosensitive properties: preparation, characterization and application in a vaginal drug delivery system

Lack of mucoadhesive properties is the major drawback to poloxamer 407 (F127)-based in situ hydrogels for mucosal administration. The objective of the present study was to construct a novel mucoadhesive and thermosensitive in situ hydrogel drug delivery system based on an amino-functionalized poloxamer for vaginal administration. First, amino-functionalized poloxamer 407 (F127-NH2) was synthesized and characterized with respect to its micellization behavior and interaction with mucin. Then using acetate gossypol (AG) as model drug, AG-loaded F127-NH2-based in situ hydrogels (NFGs) were evaluated with respect to rheology, drug release, ex vivo vaginal mucosal adhesion, in vivo intravaginal retention and local irritation after vaginal administration to healthy female mice. The results show that F127-NH2 is capable of forming a thermosensitive in situ hydrogel with sustained drug release properties. An interaction between positively charged F127-NH2 and negatively charged mucin was revealed by changes in the particle size and zeta potential of mucin particles as well as an increase in the complex modulus of NFG caused by mucin. Ex vivo and in vivo fluorescence imaging and quantitative analysis of the amount of AG remaining in mouse vaginal lavage all demonstrated greater intravaginal retention of NFG than that of an unmodified F127-based in situ hydrogel. In conclusion, amino group functionalization confers valuable mucoadhesive properties on poloxamer 407.

Fabrication, characterization and evaluation of bacterial cellulose-based capsule shells for oral drug delivery

Bacterial cellulose (BC) was investigated for the first time for the preparation of capsule shells for immediate and sustained release of drugs. The prepared capsule shells were characterized using X-ray diffraction, scanning electron microscopy and Fourier transform infrared spectroscopy. The BC capsule shells were studied for drug release using an USP type-I dissolution apparatus. Irrespective of the drying method and the thickness of the BC sheet, the capsule shells displayed an immediate drug release profile. Moreover, the addition of release-retardant cellulosic polymers sustained the drug release having first-order kinetics for hydroxypropylmethylcellulose and carboxymethyl cellulose sodium with R2 values of 0.9995 and 0.9954, respectively. Furthermore, these capsules shells remained buoyant in 0.1 N HCl (pH 1.2) solution up to 12 h. This study showed that BC is a promising alternative to gelatin capsules with both immediate and sustained drug release properties depending upon the compositions of the encapsulated materials.

A green approach to dual-drug nanoformulations with targeting and synergistic effects for cancer therapy

Exploration of efficient dual-drug nanohybrids, particularly those with high drug loading, specific targeting property, and long-termed stability, is of highly importance in cancer therapy. A pH-driven coprecipitation was performed in the aqueous phase to obtain a dual-drug nanoformulation, composed of 10-hydroxycamptothecine (HCPT) nanoneedles integrated with an exterior thin layer of the methotrexate (MTX)–chitosan conjugate. The high stability of nanohybrids in water and the targeting property provided by the MTX ingredient function synergistically to the prolonged and sustained drug release property in tumor tissues and the increased cellular uptake. The cytotoxicity test illustrates that dual-drug nanoneedles possess the remarkable killing ability to HeLa cells with the combination index at 0.33 ± 0.07. After cellular internalization, the release of both drug ingredients results in an excellent anticancer activity in vivo with the minimized adverse side effects. Design of a green approach to the carrier-free, dual-drug nanoformulations enables to develop emerging drug delivery systems for cancer diagnosis and treatment.

Enzymatic hydrogelation of self-assembling peptide I4K2and its antibacterial and drug sustained-release activities

I4K2hydrogel induced by plasma amine oxidase (PAO) has antibacterial and drug sustained-release properties.

Incorporation of amoxicillin-loaded organic montmorillonite into poly(ester-urethane) urea nanofibers as a functional tissue engineering scaffold

A dual drug-loaded system is a promising alternative for the sustained drug release system and skin tissue engineering. In this study, a natural sodium montmorillonite (Na-MMT) modified by cetyl trimethyl ammonium bromide (CTAB) was prepared as a carrier to load a model drug – amoxicillin (AMX), the modified organic montmorillonite (CTAB-OMMT) loaded with AMX was marked as AMX@CTAB-OMMT and was subsequently incorporated into poly(ester-urethane) urea (PEUU) and gelatin hybrid nanofibers via electrospinning, resulting in a new drug-loaded nanofibrous scaffold (AMX@CTAB-OMMT-PU75). The scanning electron microscopy (SEM) result showed that the fiber morphology did not change after the embedding of AMX@CTAB-OMMT. Meanwhile, there was a significant increase of mechanical properties for PEUU/Gelatin hybrid nanofibers (PU75) after the incorporation of AMX@CTAB-OMMT and CTAB-OMMT. Importantly, AMX@CTAB-OMMT-PU75 nanofibers showed a kind of sustained drug release property which could be justified reasonably for the controlled release of AMX depending on the various application. The sustained release property could be identified roughly by the result of antibacterial test. The anaphylactic reaction test proved that there was no any anaphylactic reaction or inflammation on the back of rat for AMX@CTAB-OMMT-PU75 nanofibers. Consequently, the prepared drug-loaded AMX@CTAB-OMMT-PU75 nanofibrous scaffold is a promising candidate for application in the skin tissue engineering field and controlled drug release system.

Drug loaded nanoparticle coating on totally bioresorbable PLLA stents to prevent in-stent restenosis.

Biodegradable polymer poly (dl-lactide) (PDLLA) has been used as drug coating material for drug-eluting stents due to its excellent biocompatibility and sustained drug release ability. However, the uniform thin layer drug eluting coating on a stent not only inhibits the blood vessel's smooth muscle cell overgrowth but also delay the endotheliation process which is often associated with the occurrence of acute thrombosis. Therefore, in this study, we developed a novel coating method using PDLLA nanoparticles (NPs) as a coating to overcome this issue. The average 300 nm sized sirolimus-loaded PDLLA nanoparticles were prepared by a conventional emulsion solvent evaporation method. A low temperature plasma polymerization technology to graft hydrophilic polymers on to poly (l-lactide) stent was used to increase the surface coating efficiency of nanoparticles on the stent. Results showed that sirolimus-loaded nanoparticles can be successfully coated on to the stents with sustained drug release properties. In vitro cell culture study showed the drug loaded nanoparticle coating effectively inhibited the proliferation of smooth muscle cells while still allowed a faster proliferation of endothelial cells, suggesting that the new NP coated bioresorbable stents have the potential to reduce both the occurrence of in-stent restenosis and acute thrombosis. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 88-95, 2018.

Synergistic effect of chemo-photothermal for breast cancer therapy using folic acid (FA) modified zinc oxide nanosheet

Modern therapies for malignant breast cancer in clinics are not efficacious and often result in deprived patient compliance owing to squat therapeutic effectiveness and strong systemic side effects. In order to overcome this, we combined chemo-photothermal targeted therapy of breast cancer within one novel multifunctional drug delivery system. Folic Acid-functionalized polyethylene glycol coated Zinc Oxide nanosheet (FA-PEG-ZnO NS), was successfully synthesized, characterized and introduced to the drug delivery field for the first time. A doxorubicin (DOX)-loaded FA-PEG-ZnO NS based system (DOX-FA-PEG-ZnO NS) showed stimulative effect of heat, pH responsive and sustained drug release properties. Cytotoxicity experiments confirmed that combined therapy mediated the maximum rate of death in breast cancer cells compared to that of single chemotherapy or photothermal therapy. In vivo toxicity evaluation showed that the DOX-FA-PEG-ZnO NS contains minimum systemic toxicity in the mice model system. The findings of the present study provided an ideal drug delivery system for breast cancer therapy due to the advanced chemo-photothermal synergistic targeted therapy and good drug release properties of DOX-FA-PEG-ZnO NS, which could effectively avoid frequent and invasive dosing and improve patient compliance. Thus, functionalized-ZnO NS could be used as a novel nanomaterial for selective chemo-photothermal therapy.

Theranostic Bioabsorbable Bone Fixation Plate with Drug‐Layered Double Hydroxide Nanohybrids

A bioabsorbable polymeric bone plate enabled with both diagnostic and therapeutic functionalities (radiopacity and sustained drug release, respectively) is proposed. To this end, a drug-inorganic nanohybrid (RS-LDH) is examined as a theranostic agent by intercalating an anti-resorptive bone remodeling drug, risedronate (RS) into a layered double hydroxide (LDH) via an ion-exchange reaction. The RS-LDH is prepared as a sheet with a biodegradable polymer, poly(lactic-co-glycolic acid), and is then attached onto the clinically approved bioabsorbable bone plate to produce the theranostic plate. Because of the presence of the metals in the LDH, the theranostic plate results in discernible in vivo X-ray images for up to four weeks after implantation. Concurrently, bone regeneration is also significantly improved compared with the other control groups, likely because of this material's sustained drug-release property. The theranostic plate is also largely biocompatible, similar to the plate already approved for clinical use. It is concluded that the combination of a biodegradable bone plate with RS-LDH nanohybrids can constitute a promising system with theranostic ability in both X-ray diagnosis and expedited bone repair.

Reconstituted high density lipoprotein mediated targeted co-delivery of HZ08 and paclitaxel enhances the efficacy of paclitaxel in multidrug-resistant MCF-7 breast cancer cells

In the past decades, reconstituted high density lipoprotein (rHDL) has been successfully developed as a drug carrier since the enhanced HDL-lipids uptake is demonstrated in several human cancers. In this paper, rHDL, for the first time, was utilized to co-encapsulate two hydrophobic drugs: an anticancer drug, paclitaxel (PTX), and a new reversal agent for P-gp (P-glycoprotein)-mediated multidrug resistance (MDR) of cancer, N-cyano-1-[(3,4-dimethoxyphenyl)methyl]-3,4-dihydro-6,7-dimethoxy-N′-octyl-2(1H)-isoquinoline-carboximidamide (HZ08). We proposed this drug co-delivery strategy to reverse PTX resistance. The study aimed to develop a biomimetic nanovector, reconstituted high density lipoprotein (rHDL), mediating targeted PTX-HZ08 delivery for cancer therapy. Using sodium cholate dialysis method, we successfully formulated dual-agent co-delivering rHDL nanoparticles (PTX-HZ08-rHDL NPs) with a typical spherical morphology, well-distributed size (~100nm), high drug encapsulation efficiency (approximately 90%), sustained drug release properties and exceptional stability even after storage for 1month or incubation in 10% fetal bovine serum (FBS) DMEM for up to 2days. Results demonstrated that PTX-HZ08-rHDL NPs significantly enhanced anticancer efficacy in vitro, including higher cytotoxicity and better ability to induce cell apoptosis against both PTX-sensitive and -resistant MCF-7 human breast cancer cell lines (MCF-7 and MCF-7/PTX cells). Mechanism studies demonstrated that these improvements could be correlated with increased cellular uptake of PTX mediated by scavenger receptor class B type I (SR-BI) as well as prolonged intracellular retention of PTX due to the HZ08 mediated drug-efflux inhibition. In addition, in vivo investigation showed that the PTX-HZ08-rHDL NPs were substantially safer, have higher tumor-targeted capacity and have stronger antitumor activity than the corresponding dosage of paclitaxel injection. These findings suggested that rHDL NPs could be an ideal tumor-targeted nanovector for simultaneous transfer of insoluble anticancer drug and drug resistance reversal agents. The PTX-HZ08-rHDL NPs co-delivery system might be a new promising strategy to overcome tumor drug resistance.

TAT Peptide-Conjugated Magnetic PLA-PEG Nanocapsules for the Targeted Delivery of Paclitaxel: In Vitro and Cell Studies.

Paclitaxel (PTX) and organophilic iron oxide nanocrystals of 7nm average size were co-encapsulated in the oily core of poly(lactide)-poly(ethyleneglycol) (PLA-PEG) nanocapsules in order to develop magnetically responsive nanocarriers of PTX. The nanocapsules were prepared by a solvent displacement technique and exhibited satisfactory drug and iron oxide loading efficiency, high colloidal stability, and sustained drug release properties. Drug release also proved responsive to an alternating magnetic field. Magnetophoresis experiments showed that the magnetic responsiveness of the nanocapsules depended on their SPION content. The PTX-loaded nanocapsules exhibited comparable to free PTX cytotoxicity against the A549 lung cancer cell line at 24h of incubation but higher cytotoxicity than free drug at 48h of incubation. The conjugation of a cysteine-modified TAT peptide (HCys-Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-NH2) on the surface of the nanocapsules resulted to highly increased uptake of nanocapsules by cancer cells, as well as to profound improvement of their cytotoxicity against the cancer cells. The results obtained justify further investigation of the prospects of these multifunctional PLA-PEG nanocapsules as a targeted delivery system of paclitaxel.

Bioactive SiO2-CaO-P2O5 hollow nanospheres for drug delivery

Hollow nanospherical bioactive glasses have attracted much interest in the recent years because of their important applications in drug delivery and hard tissue repair. Herein, we developed a facile method to fabricate bioactive SiO2-CaO-P2O5 (SCP) hollow nanospheres using polystyrene (PS) nanospheres as the hard template. The removal of PS templates by heating produced almost monodispersed hollow SCP nanospheres with an inner cavity of 210nm, making them suitable for drug delivery. The impact of the glass composition on the formation of hollow SCP nanospheres was investigated in detail. High drug-loading capacity and sustained multistep release of theophylline in the SCP nanospheres were achieved. Furthermore, the SCP nanospheres exhibited apatite-forming ability when immersed in a simulated body fluid. Cytotoxicity of SCP nanospheres on live cells has been evaluated. The SCP hollow nanospheres with sustained drug release property and bioactivity are promising new-generation biomaterials.

Formulation and development of ophthalmic in situ gel for the treatment ocular inflammation and infection using application of quality by design concept

Context: The conventional liquid ophthalmic delivery systems exhibit short pre-corneal residence time and the relative impermeability to the cornea which leads to poor ocular bioavailability.Objective: The aim of this study was to apply quality by design (QbD) for development of dexamethasone sodium phosphate (DSP) and tobramycin sulfate (TS)-loaded thermoresponsive ophthalmic in situ gel containing Poloxamer 407 and hydroxyl propyl methyl cellulose (HPMC) K4M for prolonging the pre-corneal residence time, ocular bioavability and decreases the frequency of administration of dosage form. The material attributes and the critical quality attributes (CQA) of the in situ gel were identified. Central composite design (CCD) was adopted to optimize the formulation.Materials and methods: The ophthalmic in situ forming gels were prepared by cold method. Materials attributes were the amount of Poloxamer 407 and HPMC and CQA identified were Gel strength, mucoadhesive index, gelation temperature and % of drug release of both drug.Results and discussion: Optimized batch (F*) containing 16.75% poloxamer 407 and 0.54% HPMC K4M were exhibited all results in acceptable limits. Compared with the marketed formulation, optimized in situ gel showed delayed Tmax, improved Cmax and AUC in rabbit aqueous humor, suggesting the sustained drug release and better corneal penetration and absorption.Conclusion: According to the study, it could be concluded that DSP and TS would be successfully formulated as in situ gelling mucoadhesive system for the treatment of steroid responsive eye infections with the properties of sustained drug release, prolonged ocular retention and improved corneal penetration.

Novel synthesis of AB-type carbonated hydroxyapatite hierarchical microstructures with sustained drug delivery properties

In this study, AB-type carbonated hydroxyapatite (CHAp) nanosheet-assembled hollow microstructures were rapidly synthesized via a hydrothermal process without sintering. Urea was employed as both a pH adjusting agent and a CO32− source during hydrothermal reaction. The influence of hydrothermal time on the final morphologies of the products was systematically investigated. The as-prepared CHAp hollow microstructures with a diameter of about 3–4 μm consist of numerous radially oriented CHAp nanosheets as building units with an average thickness of about 10 nm. The morphology of the product can vary from a hollow microstructure to a solid dandelion-like structure with increasing hydrothermal time. Possible mechanisms for the formation of a nanosheet-assembled CHAp hollow microstructure and a solid dandelion-like microstructure in the presence of both urea and ethylenediaminetetraacetic acid (EDTA) are illustrated. Moreover, the as-prepared CHAp hollow microstructures exhibit a high drug loading capacity and sustained drug release properties.

Formulation and evaluation of transdermal composite films of chitosan-montmorillonite for the delivery of curcumin.

Composite transdermal films of chitosan (CS)/montmorillonite K 10 (MMT) clay were prepared for the delivery of curcumin. CS/MMT films were evaluated for various physicochemical parameters. The films were characterized by Fourier transform infrared spectroscopy and X-ray diffraction analysis. Water uptake and swelling ratio of the films was found to decrease with increase in concentration of clay. Mechanical properties of the films were assessed in terms of tensile strength and extensibility using texture analyzer. Increase in tensile strength and reduction in extensibility was reported with increase in the clay content. This was attributed to the formation of intercalated structure and restriction in mobility of CS polymeric chains with the inclusion of clay particles. In vitro drug release study on transdermal films indicated pronounced sustained release of curcumin by the incorporation of clay particles in the CS polymer matrix. Stability study indicated no significant effect on physicochemical properties of films kept at 40°C and 75% RH for 3 months. Overall CS/MMT composite transdermal films exhibited improved mechanical and sustained drug release properties.

Synthesis of water-dispersible silicon-containing hydroxyapatite nanoparticles with adjustable degradation rates and their applications as pH-responsive drug carriers

An environmentally friendly method was developed to synthesize water-dispersible Si-HAp nanoparticles with adjustable degradation rates, high loading capacities for anticancer drugs, and sustained and pH-dependent drug release properties.

Enhanced antitumoral activity of doxorubicin against lung cancer cells using biodegradable poly(butylcyanoacrylate) nanoparticles.

Doxorubicin (Dox) is widely used for the combined chemotherapy of solid tumors. However, the use of these drug associations in lung cancer has low antitumor efficacy. To improve its efficacious delivery and activity in lung adenocarcinoma cells, we developed a biodegradable and noncytotoxic nanoplatform based on biodegradable poly(butylcyanoacrylate) (PBCA). The reproducible formulation method was based on an anionic polymerization process of the PBCA monomer, with the antitumor drug being entrapped within the nanoparticle (NP) matrix during its formation. Improved drug-entrapment efficiencies and sustained (biphasic) drug-release properties were made possible by taking advantage of the synthesis conditions (drug, monomer, and surfactant-agent concentrations). Dox-loaded NPs significantly enhanced cellular uptake of the drug in the A549 and LL/2 lung cancer cell lines, leading to a significant improvement of the drug’s antitumoral activity. In vivo studies demonstrated that Dox-loaded NPs clearly reduced tumor volumes and increased mouse-survival rates compared to the free drug. These results demonstrated that PBCA NPs may be used to optimize the antitumor activity of Dox, thus exhibiting a potential application in chemotherapy against lung adenocarcinoma.

Synthesis of folate- pegylated polyester nanoparticles encapsulating ixabepilone for targeting folate receptor overexpressing breast cancer cells.

The aim of this study was the preparation of novel polyester nanoparticles based on folic acid (FA)-functionalized poly(ethylene glycol)-poly(propylene succinate) (PEG-PPSu) copolymer and loaded with the new anticancer drug ixabepilone (IXA). These nanoparticles may serve as a more selective (targeted) treatment of breast cancer tumors overexpressing the folate receptor. The synthesized materials were characterized by (1)H-NMR, FTIR, XRD and DSC. The nanoparticles were prepared by a double emulsification and solvent evaporation method and characterized with regard to their morphology by scanning electron microscopy, drug loading with HPLC-UV and size by dynamic light scattering. An average size of 195 nm and satisfactory drug loading efficiency (3.5%) were observed. XRD data indicated that IXA was incorporated into nanoparticles in amorphous form. The nanoparticles exhibited sustained drug release properties in vitro. Based on in vitro cytotoxicity studies, the blank FA-PEG-PPSu nanoparticles were found to be non-toxic to the cells. Fluorescent nanoparticles were prepared by conjugating Rhodanine B to PEG-PPSu, and live cell, fluorescence, confocal microscopy was applied in order to demonstrate the ability of FA-PEG-PPSu nanoparticles to enter into human breast cancer cells expressing the folate receptor.

Dual-Ligand Modified Polymer-Lipid Hybrid Nanoparticles for Docetaxel Targeting Delivery to Her2/neu Overexpressed Human Breast Cancer Cells.

In this study, a dual-ligand polymer-lipid hybrid nanoparticle drug delivery vehicle comprised of an anti-HER2/neu peptide (AHNP) mimic with a modified HIV-1 Tat (mTAT) was established for the targeted treatment of Her2/neu-overexpressing cells. The resultant dual-ligand hybrid nanoparticles (NPs) consisted of a poly(lactide-co-glycolide) core, a near 90% surface coverage of the lipid monolayer, and a 5.7 nm hydrated polyethylene glycol shell. Ligand density optimization study revealed that cellular uptake efficiency of the hybrid NPs could be manipulated by controlling the surface-ligand densities. Furthermore, the cell uptake kinetics and mechanism studies showed that the dual-ligand modifications of hybrid NPs altered the cellular uptake pathway from caveolae-mediated endocytosis (CvME) to the multiple endocytic pathways, which would significantly enhance the NP internalization. Upon the systemic investigation of the cellular uptake behavior of dual-ligand hybrid NPs, docetaxel (DTX), a hydrophobic anticancer drug, was successfully encapsulated into dual-ligand hybrid NPs with high drug loading for Her2/neu-overexpressing SK-BR-3 breast cancer cell treatment. The DTX-loaded dual-ligand hybrid NPs showed a decreased burst release and a more gradual sustained drug release property. Because of the synergistic effect of dual-ligand modification, DTX-loaded dual-ligand hybrid NPs exerted substantially better therapeutic potency against SK-BR-3 cancer cells than other NP formulations and free DTX drugs. These results demonstrate that the dual-ligand hybrid NPs could be a promising vehicle for targeted drug delivery to treat breast cancer.

A simple way to synthesize 3D hierarchical HAp porous microspheres with sustained drug release

In this paper, a simple and environmentally friendly strategy was developed to synthesize the sphere-like hierarchical structures of HAp which was transformed by using flower-like CaHPO4 as a precursor in NaOH solution. Self-assembly flower-like CaHPO4 can be synthesized in mixed solvents of water and ethanol via microwave-assisted method. The effects of the reaction conditions on the morphology of the product were investigated and a possible formation mechanism was proposed. Furthermore, CaHPO4 microflowers can be transformed to HAp with sphere-like hierarchical structure with the assistance of microwave irradiation. These HAp porous microspheres exhibited high drug-loading capacity and sustained drug release properties due to their novel 3D hierarchical mesoporous structures and high specific surface area. Our study indicated that the fabricated hierarchical HAp porous microspheres might be a potential candidate as drug-delivery biomaterials for hard tissue repair.