Controlled Drug Release Capability Research Articles

Versatile Mechanically Tunable Hydrogels for Therapeutic Delivery Applications.

Hydrogels provide a versatile platform for biomedical material fabrication that can be structurally and mechanically fine-tuned to various tissues and applications. Applications of hydrogels in biomedicine range from highly dynamic injectable hydrogels that can flow through syringe needles and maintain or recover their structure after extrusion to solid-like wound-healing patches that need to be stretchable while providing a selective physical barrier. In this study, a toolbox is designed using thermo-responsive poly(N-isopropylacrylamide) (PNIPAM) polymeric matrices and nanocelluloses as reinforcing agent to obtain biocompatible hydrogels with altering mechanical properties, from a liquid injectable to a solid-like elastic hydrogel. The liquid hydrogels possess low viscosity and shear-thinning properties at 25 °C, which allows facile injection at room temperature, while they become viscoelastic gels at body temperature. In contrast, the covalently cross-linked solid-like hydrogels exhibit enhanced viscoelasticity. The liquid hydrogels are biocompatible and are able to delay the in vitro release and maintain the bioactivity of model drugs. The antimicrobial agent loaded solid-like hydrogels are effective against typical wound-associated pathogens. This work presents a simple method of tuning hydrogel mechanical strength to easily adapt to applications in different soft tissues and broaden the potential of renewable bio-nanoparticles in hybrid biomaterials with controlled drug releasecapabilities.

Recent advances in biomedical applications of carbon and graphene quantum dots: A review.

The carbon-based nanostructures have led to the development of theranostic nanoplatforms for simultaneous diagnosis and therapy due to their effective cell membrane-penetration ability, low degree of cytotoxicity, excellent pore volume, substantial chemical stability, and reactive surface. In the last few years, extensive efforts were made to design multifunctional nanoplatform strategies based on carbon nanostructures, involving multimodal imaging, controlled drug release capabilities, sensing in vitro, efficient drug loading capacity, and therapy. Carbon and graphene quantum dots (CQDs and GQDs) were the recent entrants, contingently being assessed for drug delivery and bioimaging. With the advancements, these quantum dots have ignited remarkable research interest and are now widely evaluated for diagnosis, bioimaging, sensing, and drug delivery applications. The last decade has witnessed their remarkable electrical, optical, and biocompatible properties since their inception. It is presumed that both of them have high potential as drug carriers and would serve as the next generation of approaches to address numerous unresolved therapeutic challenges. This review examined the recent advances of CQD and GQD based drug delivery applications, challenges, and future perspectives to pave the way for further studies in the future.

Fabrication of Quercetin-Functionalized Morpholine and Pyridine Motifs-Laden Silk Fibroin Nanofibers for Effective Wound Healing in Preclinical Study.

Choosing suitable wound dressings is crucial for effective wound healing. Spun scaffolds with bioactive molecule functionalization are gaining attention as a promising approach to expedite tissue repair and regeneration. Here, we present the synthesis of novel multifunctional quercetin with morpholine and pyridine functional motifs (QFM) embedded in silk fibroin (SF)-spun fibers (SF-QFM) for preclinical skin repair therapies. The verification of the novel QFM structural arrangement was characterized using ATR-FTIR, NMR, and ESI-MS spectroscopy analysis. Extensive characterization of the spun SF-QFM fibrous mats revealed their excellent antibacterial and antioxidant properties, biocompatibility, biodegradability, and remarkable mechanical and controlled drug release capabilities. SF-QFM mats were studied for drug release in pH 7.4 PBS over 72 h. The QFM-controlled release is mainly driven by diffusion and follows Fickian's law. Significant QFM release (40%) occurred within the first 6 h, with a total release of 79% at the end of 72 h, which is considered beneficial in effectively reducing bacterial load and helping expedite the healing process. Interestingly, the SF-QFM-spun mat demonstrated significantly improved NIH 3T3 cell proliferation and migration compared to the pure SF mat, as evidenced by the complete migration of NIH 3T3 cells within 24 h in the scratch assay. Furthermore, the in vivo outcome of SF-QFM was demonstrated by the regeneration of fresh fibroblasts and the realignment of collagen fibers deposition at 9 days post-operation in a preclinical rat full-thickness skin defect model. Our findings collectively indicate that the SF-QFM electrospun nanofiber scaffolds hold significant capability as a cost-effective and efficient bioactive spun architecture for use in wound healing applications.

Recent Progress in Implantable Drug Delivery Systems.

In recent years, tremendous effort is devoted to developing platforms, such as implantable drug delivery systems (IDDSs), with temporally and spatially controlled drug release capabilities and improved adherence. IDDSs have multiple advantages: i) the timing and location of drug delivery can be controlled by patients using specific stimuli (light, sound, electricity, magnetism, etc.). Some intelligent "closed-loop" IDDS can even realize self-management without human participation. ii) IDDSs enable continuous and stable delivery of drugs over a long period (months to years) and iii) to administer drugs directly to the lesion, thereby helping reduce dosage and side effects. iv) IDDSs enable personalized drug delivery according to patient needs. The high demand for such systems has prompted scientists to make efforts to develop intelligent IDDS. In this review, several common stimulus-responsive mechanisms including endogenous (e.g., pH, reactive oxygen species, proteins, etc.) and exogenous stimuli (e.g., light, sound, electricity, magnetism, etc.), are given in detail. Besides, several types of IDDS reported in recent years are reviewed, including various stimulus-responsive systems based on the above mechanisms, radio frequency-controlled IDDS, "closed-loop" IDDS, self-powered IDDS, etc. Finally, the advantages and disadvantages of various IDDS, bottleneck problems, and possible solutions are analyzed to provide directions for subsequent research.

Graphene Oxide Nanostructures as Nanoplatforms for Delivering Natural Therapeutic Agents: Applications in Cancer Treatment, Bacterial Infections, and Bone Regeneration Medicine.

Graphene, fullerenes, diamond, carbon nanotubes, and carbon dots are just a few of the carbon-based nanomaterials that have gained enormous popularity in a variety of scientific disciplines and industrial uses. As a two-dimensional material in the creation of therapeutic delivery systems for many illnesses, nanosized graphene oxide (NGO) is now garnering a large amount of attention among these materials. In addition to other benefits, NGO functions as a drug nanocarrier with remarkable biocompatibility, high pharmaceutical loading capacity, controlled drug release capability, biological imaging efficiency, multifunctional nanoplatform properties, and the power to increase the therapeutic efficacy of loaded agents. Thus, NGO is a perfect nanoplatform for the development of drug delivery systems (DDSs) to both detect and treat a variety of ailments. This review article's main focus is on investigating surface functionality, drug-loading methods, and drug release patterns designed particularly for smart delivery systems. The paper also examines the relevance of using NGOs to build DDSs and considers prospective uses in the treatment of diseases including cancer, infection by bacteria, and bone regeneration medicine. These factors cover the use of naturally occurring medicinal substances produced from plant-based sources.

A self-healable and injectable hydrogel for pH-responsive doxorubicin drug delivery in vitro and in vivo for colon cancer treatment

Hydrogels are three-dimensional solid-like structures with a wide range of applications in drug transport, tissue engineering, wound dressing, etc. We developed herein a new hydrogel by mixing 5′-guanosine monophosphate (5′-GMP) disodium salt (16 mM) and 1,4,5,8-naphthalene tetracarboxylic acid tetra potassium salt (NAP) (4 mM) in 4:1 (GMP:NAP) stoichiometry in aqueous media (pH ∼4 at 25 °C). The mechanical properties of the resulting hydrogel were investigated by rheological studies, which showed that the hydrogel formed at pH 4 is the most stable [storage modulus (Gꞌ) of ∼4000 Pa] and has higher endurance for the oscillatory strain (20% strain). Spectroscopic investigations provided insights into the unique self-assembly of 5′-GMP and NAP. Further, the composite exhibited pH-responsive hydrogelation over the pH range of 3–6, and the gel was transformed into a sol form at pH > 5. This stimuli-sensitive nature of the hydrogel was then exploited for the encapsulation and efficacious delivery of an anticancer drug, doxorubicin (DOX), specifically toward the colorectal cancer. Microscopic studies revealed the presence of a regular entangled fibrillar network for the hydrogels, which allowed for its exceptionally high drug loading capacity. The controlled release of DOX from the hydrogel was then studied at the physiological pH of the gastrointestinal tract, i.e. pH ∼7.4. The DOX-loaded hydrogel (DOX-Gel) exhibited a ∼82% release of DOX over 100 h at pH ∼7.4. The enhanced cellular toxicity of DOX was observed in CT-26 murine colorectal carcinoma cell lines treated with the DOX-loaded hydrogel compared to DOX only as manifested from the fluorescence-activated cell sortinganalyses and fluorescence microscopic studies. The fluorescence-activated cell sorting analysis showed a ∼4.5-fold increase in the drug internalization for the DOX-Gel as compared to DOX only formulations. The co-localization of DOX into the cell nucleus was confirmed from confocal microscopy. The in vivo drug delivery efficacy of this pH-responsive hydrogel was further assessed on an animal tumor model, Balb/c mice (n = 9). A significant regression of ∼87.5% in the tumor volume was observed after 21 days of DOX-gel administration, in contrast to DOX only formulation, which showed only a ∼46.0% regression in the tumor volume. The blood reports of the non-treated control mice and the mice treated with DOX only indicated a metastatic behavior in comparison with the mice treated with the DOX-Gel. This, the present system, is a self-healable, injectable hydrogel, which makes it an ideal drug delivery vehicle with stimuli-responsive controlled drug release capabilities even in vivo.

Establishment of ultrasound-responsive SonoBacteriaBot for targeted drug delivery and controlled release.

Bacteria-driven biohybrid microbots have shown great potential in cancer treatment. However, how precisely controlling drug release at the tumor site is still an issue. To overcome the limitation of this system, we proposed the ultrasound-responsive SonoBacteriaBot (DOX-PFP-PLGA@EcM). Doxorubicin (DOX) and perfluoro-n-pentane (PFP) were encapsulated in polylactic acid-glycolic acid (PLGA) to form ultrasound-responsive DOX-PFP-PLGA nanodroplets. Then, DOX-PFP-PLGA@EcM is created by DOX-PFP-PLGA amide-bonded to the surface of E. coli MG1655 (EcM). The DOX-PFP-PLGA@EcM was proved to have the characteristics of high tumor-targeting efficiency, controlled drug release capability, and ultrasound imaging. Based on the acoustic phase change function of nanodroplets, DOX-PFP-PLGA@EcM enhance the signal of US imaging after ultrasound irradiation. Meanwhile, the DOX loaded into DOX-PFP-PLGA@EcM can be released. After being intravenously injected, DOX-PFP-PLGA@EcM can efficiently accumulate in tumors without causing harm to critical organs. In conclusion, the SonoBacteriaBot has significant benefits in real-time monitoring and controlled drug release, which has significant potential applications for therapeutic drug delivery in clinical settings.

Design and optimization of gatifloxacin loaded polyvinyl alcohol nanofiber for the treatment of dry eye infection: In vitro and in vivo evaluation

According to a clinical report, nearly 50% of dry eye patients have an elevated risk of ocular infections and inflammations. Nanofiber could serve as a potential vehicle for treating anterior ocular disease because of its sterile nature, known solubility enhancing ability, capacity to carry multiple drugs, and controlled drug release capability, which can minimize overall dose and dosing frequency. As a result, the goal of this study was to assess the therapeutic potential of Gatifloxacin (GAF) loaded Polyvinyl alcohol (PVA) nanofiber for the treatment of dry eye syndrome with infection. Towards in vitro assessment, optimized nanofiber was characterized through surface imaging, swelling, release behavior, sterility, residual solvent, and degradation studies. Goat cornea was used to determine trans corneal penetrability. Therapeutic performance of the optimized nanofibers was assessed in a dry eye animal model. Results showed that applied potential of 12 kV, the flow rate of 3 μl/min, and plate to collector distance of 20 cm were the optimized electrospinning parameters for bead-free uniform fiber of around 200 nm. Longer precorneal contact time and biphasic release behavior, with an initial burst phase followed by a 7-h controlled release profile, are thought to reduce the need for frequent dosing to manage dry eye issues. Additionally, there was partial tear volume restitution and the tear ferns revival after 36h. Overall, the in-vitro and in-vivo results suggested that the developed product could be a viable alternative to manage dry eye infectious syndrome with less frequent dosing.

Dual-functional SFP/PAN based nano drug release system for treatment and nutrients

Nano drug delivery systems can control the ordered release of drugs. To achieve the target of supplying therapeutics and nutrients at the same time, a novel nano drug delivery system with a core–shell structure was prepared by coaxial electrospinning. Polyacrylonitrile (PAN) has been used to produce a drug release scaffold in the shell section, mixed with absorbable silk fibroin peptide (SFP) as a nutrient. Ciprofloxacin (CPFX), a broad-spectrum antibiotic, was used as the core, as well as an antibacterial agent. Owing to its low molecular weight, using a pure SFP thin solution to manufacture nanofibers by electrospinning is still technically challenging. Thus, different ratios of PAN to SFP were used in the shell electrospinning solution. In this research, a novel nano dual-functionality drug delivery system has been successfully prepared. In vitro testing demonstrated that nanofibers could supply more nutrients with increasing SFP in shell solutions; however, the ability to maintain controlled release was reduced. It was found that the nanofiber membrane had the best controlled drug release capability for a PAN-to-SFP mass ratio of 95:5. Overall, most ciprofloxacin was released in the first 12 h, while the release of SFP was constant throughout the first 24 h. Our modeling demonstrated that the release of CPFX and SFP is best described using a first-order kinetic model. The developed drug delivery system is designed to release antimicrobial drugs in a controlled manner and provide absorbable nutrients simultaneously.

HPMA copolymer-antibody constructs in neoplastic treatment: an overview of therapeutics, targeted diagnostics, and drug-free systems

In the past decades, nanosized drug delivery systems based on N-(2-hydroxypropyl)methacrylamide copolymers (pHPMA) have gained increasing attention in nanomedicine field due to their hydrophilicity, versatility, biocompatibility, non-toxicity, and non-immunogenicity. Indeed, pHPMA nanosystems with various controlled drug release capabilities inside targeted tissues or cells have been intensively studied. This paper summarizes recent advances in the design and application of pHPMA conjugates with specific antibodies or their fragments, focusing predominantly on the systems for the cancer therapy, particularly, the mechanisms of action of therapeutic antibodies, the approaches of their modification and subsequent attachment of pHPMA and their conjugates with diverse active moieties. Finally, we highlight the major biomedical applications of these antibody-polymer-drug conjugates and consider directions of possible development over the coming decade.

Biomolecule-Conjugated Macroporous Hydrogels for Biomedical Applications.

Biomolecule-conjugated macroporous hydrogels have been investigated in the fields of bioseparation, biocatalysts, bioreactors, cell therapy, tissue regeneration, and environmental applications. This review focuses on different types of biological molecules that have been conjugated on macroporous hydrogels. A variety of techniques are available for the fabrication of macroporous hydrogels and attachment of biomolecules. Natural polymers, ECM components, growth factors, peptides, and proteins have been widely used for the functionalization of macroporous hydrogels for various biomedical applications. The major areas benefited by the incorporation of these biomolecules are separation of cells and biomolecules (e.g., antibodies), tissue repair and regeneration (e.g., peptides and ECM molecules), biocatalysts (e.g., enzymes), and control of environmental pollution. Additionally, functionalization of macroporous hydrogels with chemical drugs has demonstrated their controlled drug release capabilities. Moreover, clinically available biofunctionalized macroporous polymeric products have been briefly discussed.

In-situ crosslinked wet spun collagen triple helices with nanoscale-regulated ciprofloxacin release capability

The design of antibacterial-releasing coatings or wrapping materials with controlled drug release capability is a promising strategy to minimise risks of infection and medical device failure in vivo. Collagen fibres have been employed as medical device building block, although they still fail to display controlled release capability, competitive wet-state mechanical properties, and retained triple helix organisation. We investigated this challenge by pursuing a multiscale design approach integrating drug encapsulation, in-situ covalent crosslinking and fibre spinning. By selecting ciprofloxacin (Cip) as a typical antibacterial drug, wet spinning was selected as a triple helix-friendly route towards Cip-encapsulated collagen fibres; whilst in situ crosslinking of fibre-forming triple helices with 1,3 phenylenediacetic acid (Ph) was hypothesised to yield Ph-Cip {\pi}-{\pi} stacking aromatic interactions and enable controlled drug release. Higher tensile modulus and strength were measured in Ph crosslinked fibres compared to state-of-the-art carbodiimide crosslinked controls. Cip-encapsulated Ph-crosslinked fibres revealed decreased elongation at break and significantly-enhanced drug retention in vitro with respect to Cip-free variants and carbodiimide-crosslinked controls, respectively. This multiscale manufacturing strategy provides new insight aiming at wet spun collagen triple helices with nanoscale-regulated tensile properties and drug release capability.

Nano-Carriers Based on pH-Sensitive Star-Shaped Copolymers for Drug-Controlled Release.

Polymeric nano-carriers are considered as promising tools in biomedical applications due to multiple attractive characteristics including their low toxicity, high loading capacity, controlled drug release capabilities, and highly tunable chemical properties. Here, a series of pH-sensitive star-shaped copolymers, Ad-P[(EMA-co-MAA)-b-PPEGMA]4, was prepared via electron transfer atom radical polymerization (ARGETE ATRP) and selective hydrolysis. These star-shaped copolymers can be self-assembled into micelles (Dh = 150–160 nm) and their critical micelle concentrations (CMC) were estimated to be 3.9–5.0 mg/L. The pH-sensitiveness of the micelles was evidenced by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The maximal paclitaxel (PTX) loading efficiency (DLC) and entrapment efficiency (EE) were 18.9% and 36%, respectively. In vitro release studies revealed that about 19% of the PTX released at an acidic condition of pH 1.2 over 70 h, whereas more than 70% was released within the same time interval at pH 6.8. In vitro cytotoxicity suggested that the low cytotoxicity of the blank micelles, while the PTX-loaded micelles providing the cytotoxicity close to that of free PTX. These results indicated that this novel pH-sensitive nano-carriers have great potential applications for oral drug-controlled release.

Shape memory hydroxypropyl cellulose-g-poly (ε-caprolactone) networks with controlled drug release capabilities

Hydroxypropyl cellulose-g-poly (e-caprolactone) (HPC-g-PCL) derived networks from different lengths of PCL side chains have been prepared by crosslinking HPC-g-PCL, providing (X(HPC-g-PCL)) films with different gel contents, crystallinity, and morphology. Two networks with different e-cCaprolactone (CL) content (95 and 98%) named X(HPC-g-PCL)-95 and X(HPC-g-PCL)-98 were used for further study of thermo-mechanical properties and shape memory behavior. Young’s modulus (E), elongation at break (eb %) and tensile strength (σm) were examined at three different temperatures 22, 37 and 65 °C. The results revealed that E values significantly were controlled by crystallinity as well as crosslink density depending on the temperatures. Complete shape recovery was observed for both samples once the degree of crosslinking was increased over 95%, while a narrower recovery temperature ranges from 39 to 41 °C was found for the X(HPC-g-PCL)-98 sample. The shape fixity results showed a great dependence on the molecular weight of PCL. Therefore, the X (HPC-g-PCL)-98 sample demonstrated an excellent shape fixation. Naproxen-loaded shape memory films prepared using either the in situ (before crosslinking) or swelling (after crosslinking) methods (3 and 10 wt%), were also described as a model for controlled drug release device. The chemical composition of drug-loaded networks, drug concentration and the incorporation method greatly affected the crosslink density, morphology and mechanical properties. Importantly, loading via the in situ method resulted possibility to adjust the amount of incorporated drug and fast subsequent release, while drug-loaded films by the swelling method exhibited an initial burst release. Both networks exhibited slow sustained release of naproxen over two months.

Reduction-sensitive CD44 receptor-targeted hyaluronic acid derivative micelles for doxorubicin delivery.

IntroductionA reduction-sensitive CD44-positive tumor-targetable drug delivery system for doxorubicin (DOX) delivery was developed based on hyaluronic acid (HA)-grafted polymers.Materials and methodsHA was conjugated with folic acid (FA) via a reduction-sensitive disulfide linkage to form an amphiphilic polymer (HA-ss-FA). The chemical structure of HA-ss-FA was analyzed by ultraviolet spectroscopy, Fourier transform infrared spectroscopy, and 1H nuclear magnetic resonance (NMR) spectroscopy. The molecular weight of HA-ss-FA was determined by high-performance gel permeation chromatography. Blank HA-ss-FA micelles and DOX-loaded micelles were prepared and characterized. The reduction responsibility, cellular uptake, and in vivo biodistribution of HA-ss-FA micelles were investigated.ResultsDOX-loaded micelles were of high encapsulation efficiency (88.09%), high drug-loading content (22.70%), appropriate mean diameter (100–120 nm), narrow size distribution, and negative zeta potential (−6.7 to −31.5 mV). The DOX release from the micelles was significantly enhanced in reduction environment compared to normal environment. The result of in vitro cytotoxicity assay indicated that the blank micelles were of low toxicity and good biocompatibility and the cell viabilities were >100% with the concentration of HA-ss-FA from 18.75 to 600.00 μg/mL. Cellular uptake and in vivo biodistribution studies showed that DOX-loaded micelles were tumor-targetable and could significantly enhance cellular uptake by CD44 receptor-mediated endocytosis, and the cellular uptake of DOX in CD44-positve A549 cells was 1.6-fold more than that in CD44-negative L02 cells. In vivo biodistribution of HA-ss-FA micelles showed that micelles were of good in vivo tumor targetability and the fluorescence of indocyanine green (ICG)-loaded micelles was 4- to 6.6-fold stronger than free ICG within 6 h in HCCLM3 tumor-bearing nude mice.ConclusionHA-ss-FA is a promising nanocarrier with excellent biocompatibility, tumor targetability, and controlled drug release capability for delivery of chemotherapy drugs in cancer therapy.

ROS-Sensitive Polymeric Nanocarriers with Red Light-Activated Size Shrinkage for Remotely Controlled Drug Release

Drug delivery systems with remotely controlled drug release capability are rather attractive options for cancer therapy. Herein, a reactive oxygen species (ROS)-sensitive polymeric nanocarrier TK-PPE@NPCe6/DOX was explored to realize remotely controlled drug release by light-activated size shrinkage. The TK-PPE@NPCe6/DOX encapsulating chlorin e6 (Ce6) and doxorubicin (DOX) was self-assembled from an innovative ROS-sensitive polymer TK-PPE with the assistance of an amphiphilic copolymer poly(ethylene glycol)-b-poly(e-caprolactone) (PEG-b-PCL). Under the 660 nm red light irradiation, ROS generated by the encapsulated Ce6 were capable of cleaving the TK linker in situ, which resulted in the rapid degradation of the TK-PPE@NPCe6/DOX core. Consequently, the size of TK-PPE@NPCe6/DOX shrank from 154 ± 4 nm to 72 ± 3 nm, and such size shrinkage affected further triggered rapid DOX release. As evidenced by both in vitro and in vivo experiments, such ROS-sensitive polymeric nanocarriers with light-induced size shri...

Bio-derived cellulose nanofibril reinforced poly(N-isopropylacrylamide)-g-guar gum nanocomposite: An avant-garde biomaterial as a transdermal membrane

The delivery of diltiazem hydrochloride in therapeutical doses has attracted an immense research interest. However, its slower penetration through the transdermal route has stipulated to develop a competent transdermal membrane. Therefore, a nanocomposite based patch was formulated by exploring co-polymer and jute derived nano-cellulose. Poly(N-isopropylacrylamide) was grafted into guar gum (GG-g-PNIPAAm) with different feeding ratios. The co-polymer formation was authenticated by FTIR and 13C NMR spectra. The nanocomposite were prepared by incorporating nanofibre (0.5–2 wt%) into GG-g-PNIPAAm. The structural and morphological studies supported good interactions and presence of nano-cellulose on co-polymer. GG-g-PNIPAAm has showed higher thermostability than guar gum. Moreover, the addition of CNF has improved the thermo-mechanical and barrier properties of the nanocomposite. The nanocomposite containing 1 wt% CNF was found to be best performing. The patch showed in-vitro cyto-compatibility and non-irritant behaviour. The in-vitro release study of best nanocomposite revealed controlled drug release capability with 7.78 and 22.9% after 5 and 20 h, respectively.

Crosslinked chitosan coated n-HA/PA66 scaffolds with controlled drug release capability for bone tissue engineering application

Crosslinked chitosan coated n-HA/PA66 scaffolds with controlled drug release capability for bone tissue engineering application

Development of bioactive glass based scaffolds for controlled antibiotic release in bone tissue engineering via biodegradable polymer layered coating.

Highly porous 45S5 Bioglass(®)-based scaffolds coated with two polymer layers were fabricated to serve as a multifunctional device with controlled drug release capability for bone regeneration applications. An interior poly(d,l-lactide)/poly(ethylene glycol)-(polypropylene glycol)-poly(ethylene glycol) triblock copolymer (Pluronic P123) coating improved the mechanical stability of Bioglass-based scaffolds, while an exterior natural polymer (alginate or gelatin) coating served as an antibiotic drug carrier. The results showed improved mechanical properties of Bioglass-based scaffolds by the bilayer polymer coating. In addition, hydrochloride tetracycline loaded in either alginate or gelatin coatings was released rapidly at the initial stage (∼1 h), while the released rate subsequently decreased and was sustained for 14 days in phosphate buffered saline. Therefore, these layered polymer coated scaffolds exhibit attractive characteristics in terms of improved mechanical properties and controlled drug release, simultaneously with the added advantage that the drug release rate is decoupled from the intrinsic scaffold Bioglass degradation mechanism. The layered polymer coated scaffolds are of interest for drug-delivery enhanced bone regeneration applications.

Redox/pH dual stimuli-responsive biodegradable nanohydrogels with varying responses to dithiothreitol and glutathione for controlled drug release

A new type of redox/pH dual stimuli-responsive poly(methacrylic acid) (PMAA)-based nanohydrogels was prepared from methacrylic acid and N,N-bis(acryloyl)cystamine crosslinker via distillation-precipitation polymerization. The nanohydrogels could be easily degraded into individual linear short chains (Mn ≈ 1200, Mw/Mn < 1.1) in the presence of 10 mM dithiothreitol (DTT) or glutathione (GSH). Doxorubicin (DOX) as a model anti-cancer drug was high efficiently loaded into the nanohydrogels (up to 42.3 wt%) due to the strong electrostatic interactions between the amine group in doxorubicin (DOX) and the carboxyl groups in the nanohydrogels at a physiological pH. The cumulative release profile of the DOX-loaded nanohydrogels showed a low level of drug release (less than 15 wt% in 24 h) at pH 7.4, and was significantly accelerated at a lower pH (5.0) and reducing environment (over 91 wt% in 5 h), exhibiting an obvious pH/redox dual-responsive controlled drug release capability. The drug release behavior of the DOX-loaded nanohydrogels in the presence of GSH was very different from the DTT as the loaded DOX could be quickly released in the presence of GSH, but not in DTT. The possible reason is the synergic effect of reduction and charge exchange of GSH at a low pH. The dose-dependent cytotoxicity of the DOX-loaded nanohydrogels was studied by the CCK-8 assay; the DOX-loaded nanohydrogels could be taken up quickly by human glioma (U251MG cells) via endocytosis, and then biodegraded to release the loaded drugs, which exhibited a comparably anti-tumor efficacy. These nanohydrogels possess many favorable traits, such as excellent biocompatibility and biodegradability, adequate drug loading capacity, minimal drug release under an extracellular condition (non-reductive), and rapid drug release in response to the intracellular level of pH and reducing potential, which endow them as a promise candidate for delivering anti-cancer drugs.