Injectable Drug Carriers Research Articles

Selective Anticervical Cancer Injectable and Self-Healable Hydrogel Platforms Constructed of Drug-Loaded Cross-Linkable Unimolecular Micelles in a Single and Combination Therapy.

In the face of severe side effects of systemic chemotherapy used in cervical cancer, topical selective drug carriers with long-lasting effects are being sought. Hydrogels are suitable platforms, but their use is problematic in the case of delivery of hydrophobic drugs with anticancer activity. Herein, hydrogels constructed of unimolecular micelles displaying enhanced solubilization of aromatic lipophilic bioactive compounds are presented. Star-shaped poly(benzyl glycidyl ether)-block-poly(glycidyl glycerol ether) with an aryl-enriched core show high encapsulation capacity of poor water-soluble nifuratel and clotrimazole. Nifuratel attained selectivity against cervical cancer cells, whereas clotrimazole preserved its original selectivity. The combination of unimolecular micelles loaded with both drugs provided synergism; however, they were still selective against cervical cancer cells. The cross-linking of drug-loaded unimolecular micelles via dynamic boronic esters provided injectable and self-healable hydrogel drug carriers also displaying synergistic anticancer activity, suitable for intravaginal administration and assuring the effective coverage of the afflicted tissue area and efficient tissue permeability with hydrophobic bioactive compounds. Here, we show that the combination of star-shaped polyether amphiphiles and boronic ester cross-linking chemistry provides a new strategy for obtaining hydrogel platforms suitable for efficient hydrophobic drug delivery.

Liquid metal–polymer nano-microconjugations as an injectable and photo-activatable drug carrier

Nanoparticles of photoresponsive liquid–liquid phase-separation polymers complexed with liquid metals can concentrate drugs upon photoirradiation, opening up new DDS horizons.

Core-Shell Microspheres Prepared Using Coaxial Electrostatic Spray for Local Chemotherapy of Solid Tumors.

Local chemotherapy is an alternative therapeutic strategy that involves direct delivery of drugs to the tumor site. This approach avoids adverse reactions caused by the systemic distribution of drugs and enhances the tumor-suppressing effect by concentrating the drugs at the tumor site. Drug-loaded microspheres are injectable sustained-release drug carriers that are highly suitable for local chemotherapy. However, a complex preparation process is one of the main technical difficulties limiting the development of microsphere formulations. In this study, core-shell structured microspheres loaded with paclitaxel (PTX; with a core-shell structure, calcium alginate outer layer, and a poly (lactic acid-co-glycolic acid) copolymer inner layer, denoted as PTX-CA/PLGA-MS) were prepared using coaxial electrostatic spray technology and evaluated in vitro and in vivo. PTX-CA/PLGA-MS exhibited a two-stage drug release profile and enhanced anti-tumor effect in animal tumor models. Importantly, the preparation method reported in this study is simple and reduces the amount of organic solvent(s) used substantially.

Phenol-Grafted Alginate Sulfate Hydrogel as an Injectable FGF-2 Carrier.

In the field of tissue engineering, fibroblast growth factor-2 (FGF-2) effectively regenerates damaged tissue and restores its biological function. However, FGF-2 readily diffuses and degrades under physiological conditions. Therefore, methods for the sustained and localized delivery of FGF-2 are needed. Drug delivery systems using hydrogels as carriers have attracted significant interest. Injectable hydrogels with an affinity for FGF-2 are candidates for FGF-2 delivery systems. In this study, we fabricated a hydrogel from phenol-grafted alginate sulfate (AlgS-Ph) and investigated its application to the delivery of FGF-2. The hydrogel was prepared under mild conditions via horseradish peroxidase (HRP)-mediated cross-linking. Surface plasmon resonance (SPR) measurements show that the AlgS-Ph hydrogel has an affinity for FGF-2 in accordance with its degree of sulfation. Conditions for the preparation of the AlgS-Ph hydrogel, including HRP and H2O2 concentrations, are optimized so that the hydrogel can be used as an injectable drug carrier. The hydrogel shows no cytotoxicity when using 10T1/2 cells as a model cell line. The angiogenesis assay shows that FGF-2 released from the AlgS-Ph hydrogel promotes the formation of blood vessels. These results indicate that the AlgS-Ph hydrogel is a suitable candidate for the FGF-2 carrier.

Effect of relative centrifugal force on the biological properties of liquid platelet-rich fibrin produced via horizontal centrifugation.

Platelet-rich fibrin (PRF) in liquid form has shown advantages in tissue engineering including acting as injectable fillers and drug carriers. However, few studies have investigated the best relative centrifugal force (RCF) for preparing liquid PRF. The aim of the present study was to find out optimal centrifugation force for preparing liquid PRF. Liquid PRF was prepared using horizontal centrifugation (liquid H-PRF) with RCF ranging from 100g, 300g, 500g, to 700g for 8min. The volume, weight, solidification time, and tensile properties were subsequently investigated. Scanning electron microscopy (SEM) and rheologic tests were carried out to investigate the microstructure and rheologic properties of liquid H-PRF after natural polymerization. The total number, concentration, and distribution of cells within each liquid H-PRF was evaluated by complete blood count (CBC) analysis and hematoxylin-eosin staining. As RCF values increased, the volume and weight of liquid H-PRF both increased accordingly. SEM images revealed that as the centrifugal force increased, the fibrin bundles became thinner with a denser fibrin network, and rheologic tests revealed improved mechanical properties. CBC analysis demonstrated that 500g group had the highest number of leukocytes and neutrophils, whereas 100g group yielded the highest concentration of leukocytes and platelets. Furthermore, histological analysis suggests that cells obtained by 500g for 8min were most evenly distributed in liquid H-PRF. In summary, the present study provided insights into the contents of liquid H-PRF prepared at different centrifugation forces, enabling clinicians to choose proper centrifugation forces based on their needs. The present findings provide theoretical basis for clinical choice of liquid H-PRF protocol from mechanical, cell contents, and histological aspects.

Coacervate-Based Instant and Repeatable Underwater Adhesive with Anticancer and Antibacterial Properties.

Underwater adhesion is a great challenge for the development of adhesives as the attractive interfacial intermolecular interactions are usually weakened by the surface hydration layer. The coacervation process of sessile organisms like marine mussels and sandcastle worms has inspired substantial research interest in the fabrication of long-lasting underwater adhesives, but they generally suffer from time-consuming curing triggered by surrounding environmental changes and cannot reserve the adhesiveness once damaged. Herein, an instant and repeatable underwater adhesive was developed based on the coacervation of tannic acid (TA) and poly(ethylene glycol)77-b-poly(propylene glycol)29-b-poly(ethylene glycol)77 (PEG-PPG-PEG, F68), which was driven by hydrogen-bonding interaction, and the hydrophobic cores of F68 micelles offered an additional cross-linking to enhance the mechanical properties. The TA-F68 coacervates could be facilely painted on different substrates, exhibiting robust and instant underwater adhesion (with adhesion strength up to 1.1 MPa on porcine skin) and excellent repeatability (at least 1000 cycles), superior to the previously reported coacervates. Due to the biological activities of TA, the underwater adhesive displayed innate anticancer and antibacterial properties against different types of cancer cells and bacteria, showing great potential for diverse biomedical applications, such as injectable drug carriers, tissue glues, and wound dressings.

Thermoinduced aggegation of chitosan systems in perikinetic and orthokinetic regimes

Thermoresponsive colloidal chitosan systems forming the polymer structure in situ are an example of promising solutions in tissue engineering as an injectable scaffolds or drug carriers. Their application method, and thus shearing, may affect the aggregation process in accordance with the colloidal engineering approach. The aim of the study is to compare the kinetics of chitosan aggregation in the perikinetic regime (limited by Brownian motions) with the orthokinetic process carried out under the influence of an external shear field. The research was carried out using static multiple light scattering (S-MLS) and rheometric measurement techniques coupled with small-angle light scattering (Rheo-SALS). It has been found that the introduction of an external shear field (orthokinetic regime) accelerates the aggregation of chitosan systems. Simultaneously, the rotational measurements can even lead to spontaneous gelation, most likely caused by changes in the conformation of chitosan molecules, their deformation and ordering along the shear field.

Effect of crosslinking agents on drug distribution in chitosan hydrogel for targeted drug delivery to treat cancer

Due to in-situ gelation, an injectable hydrogel drug carrier has advantages over other delivery systems. Atomic simulations help to study the structure-performance relationship of drug delivery systems (DDS) considering the interaction between components, which is focused in this study. Chitosan hydrogel network is constructed using three different crosslinking agents, soaked with water, and thermal cycles are applied to estimate the critical temperatures. Subsequently, three different drug molecules are incorporated into the models separately and the distributions are observed by analyzing the trajectories of the drug molecules obtained from the simulations performed with canonical ensembles, as the distributions will affect the drug discharge. Afterward, a protein – associated with cancer is added to the supercell and the diffusion of the drug is observed in the presence of protein molecules. A better system consisting of the drug molecules and differently cross-linked hydrogels is recommended in this study in terms of the diffusivity of the drug molecules out of nine distinct systems.

Modulating sustained drug release from nanocellulose hydrogel by adjusting the inner geometry of implantable capsules

Nanocellulose hydrogel has been shown to be an excellent platform for drug delivery and it has been lately studied as an injectable drug carrier. 3D printing is an effective method for fast prototyping of pharmaceutical devices with unique shape and cavities enabling new types of controlled release. In this study, we combined the versatility of 3D printing capsules with controlled geometry and the drug release properties of nanocellulose hydrogel to accurately modulate its drug release properties. We first manufactured non-active capsules via 3D printing from biocompatible poly(lactic acid) (PLA) that limit the direction of drug diffusion. As a novel method, the capsules were filled with a drug dispersion composed of model compounds and anionic cellulose nanofiber (CNF) hydrogel. The main benefit of this device is that the release of any CNF-compatible drug can be modulated simply by modulating the inner geometry of the PLA capsule. In the study we optimized the size and shape of the capsules inner cavity and performed drug release tests with common beta blockers metoprolol and nadolol as the model compounds. The results demonstrate that the sustained release profiles provided by the CNF matrix can be accurately modulated via adjusting the geometry of the 3D printed PLA capsule, resulting in adjustable sustained release for the model compounds.

Enhanced therapeutic effect of paclitaxel with a natural polysaccharide carrier for local injection in breast cancer

The side effect and inefficiency of paclitaxel (PTX) in clinic have became the major problem in field of cancer chemotherapy. The local drug delivery constructed by injectable hydrogel has been suggested as the alternative due to its superior properties such as tumor selectivity, minimally invasive administration and sustained drug release behavior. Polysaccharides have been commonly used as a gelling agent to construct injectable hydrogel due to its wide resources, biocompatibility and bioactive functions. Here, we reported an injectable drug carrier with enhanced therapeutic effect based on Pinus koraiensis polysaccharide (PKP). The interaction, morphology and mechanical properties were studied. Interestingly, gels exhibited excellent injectable property including rapid recovery time, excellent thixotropy ability and good rheological property after injection, and these special properties make them more suitable to be constructed as an injectable drug carrier. In addition, the biocompatibility of gel was demonstrated in terms of hemolysis analysis. PTX-loaded gel showed excellent tumor inhibition effect against 4T1 and MCF-7 breast cancer cell lines in vitro, and exhibited the significant tumor growth suppression and reduced systemic toxicity in vivo. The successful construction of PTX-loaded gel demonstrates that PKP can be used as a promising carrier in local drug delivery.

Long-term delivery of alendronate through an injectable tetra-PEG hydrogel to promote osteoporosis therapy

Pharmacotherapy for hypercalcemia, which is mainly caused by osteoporosis, is an effective method to regulate the in vivo calcium equilibrium. From this perspective, the development of a minimally invasive gelling system for the prolonged local delivery of bisphosphonates has practical significance in the clinical therapy of bone osteoporosis. Here, a biocompatible and injectable hydrogel based on a uniform tetra-PEG network carrying a PEG-modified alendronate (ALN) prodrug for the localized elution and long-term sustained release of anti-osteoporotic small molecule drugs is reported. The obtained ALN-based tetra-PEG hydrogels exhibit rapid gel formation and excellent injectability, thereby allowing for the easy injection and consequent adaptation of hydrogels into the bone defects with irregular shapes, which promotes the ALN-based tetra-PEG hydrogels with depot formulation capacity for governing the on-demand release of ALN drugs and local reinforcement of bone osteoporosis at the implantation sites of animals. The findings imply that these injectable hydrogels mediate the optimized release of therapeutic cargoes and effectively promote in situ bone regeneration via minimally invasive procedures, which is effective for clinical osteoporosis therapy.

Pluronic F127 thermosensitive injectable smart hydrogels for controlled drug delivery system development

Understanding structure-property relationships is critical for the development of new drug delivery systems. This study investigates the properties of Pluronic smart hydrogel formulations for future use as injectable controlled drug carriers. The smart hydrogels promise to enhance patient compliance, decrease side effects and reduce dose and frequency. Pharmaceutically, these systems are attractive due to their unique sol-gel phase transition in the body, biocompatibility, safety and injectability as solutions before transforming into gel matrices at body temperature. We quantify the structural changes of F127 systems under controlled temperature after flow, as experienced during real bodily injection. Empirical formulae combining the coupled thermal and shear dependency are produced to aid future application of these systems. Induced structural transitions measured in-situ by small angle x-ray and neutron scattering reveal mixed oriented structures that can be exploited to tailor the drug release profile.

Injectable Carrier for Zero-Order Release of Salmon Calcitonin.

Salmon calcitonin (sCT) was developed as an antiresorptive for the management of osteoporosis, a major public health threat worldwide. However, its clinical application was severely limited by its short half-life. Herein, an injectable drug carrier, that is, polylactic acid (PLA) microspheres coated with TA/PEG-sCT (TA: tannic acid. PEG-sCT: PEGylated sCT) layer-by-layer (LBL) films, was designed. An in vitro test demonstrated that, unlike previously developed drug carriers, the new carrier released PEG-sCT at a constant rate. The unique zero-order release kinetics originates from its unique drug release mechanism, that is, drug release via gradual disintegration of the dynamic TA/PEG-sCT LBL film. The small size of the PLA microspheres allows the carrier to be administrated via subcutaneous injection. An in vivo test demonstrated that a single injection of the carrier could maintain the plasma level of PEG-sCT stable for an extended period and thus induced a stable reduction in the plasma calcium level in rats. Using a rat model of osteoporosis induced by ovariectomy, it was further demonstrated that a single injection of the new carrier gave better therapeutic outcomes than daily injection of sCT of the same dose, thanks to the improved pharmacokinetic profile. Given the advantages of the new carrier, including facile subcutaneous administration, less frequent dosing, no initial burst release, no peak plasma drug level, and improved therapeutic outcomes, it is expected to have potential in long-term management of osteoporosis and other metabolic bone diseases.

One-pot fabrication of polymer micro/nano-discs via phase separation and a roll-to-roll coating process

Disc-shaped particles are one of the unique and promising shapes that can improve adhesion to interfaces and can function as the key feature in various applications; e.g. injectable drug carriers. However, most of these methods include the shape deformation process from spheres to discs using various external stimuli or require multiple processing steps, which is complicated and has limitations in terms of continuous fabrication. We herein propose a novel method combining polymer blend phase separation and a roll-to-roll coating process to continuously fabricate polymer micro/nano-discs in a one-pot manner on a large-scale. The evaporation of solvent during a roll-to-roll coating process encourages the formation of homogenous island-like domains composed of the minor component dispersed in a matrix of the major component on a water-soluble polyvinyl alcohol (PVA) film. In fact, polyvinylpyrrolidone (PVP) was chosen as the major component since it dissolves in both water and chloroform. Another polymer, polystyrene (PS), as a minor component was dissolved in chloroform with PVP. A PVP and PVA matrix film can be easily washed out by water, and micro/nano-discs of the PS minor component can be obtained in a one-pot manner. This method is shown to be capable of continuously fabricating PS micro/nano-discs at a very high rate of ∼108 particles/min. The effects of fabrication conditions, such as the blend ratio and total polymer concentration on the dimensions of the PS discs were investigated, and a maximum aspect ratio (ratio between diameter and thickness) of 6.3 (diameter ∼830 nm, thickness ∼130 nm) was demonstrated. The method proposed in this study could provide a straightforward and time-saving way to continuously fabricate micro/nano-discs via polymer phase separation and a roll-to-roll coating process.

Microfluidic fabrication of fatty alcohol-based microparticles for NIR light-triggered drug release

The development of photo-triggered drug delivery system is promising for the temporal and spatial control of drug release. However, most of the progress in photothermal drug delivery has been focused on nanosized particles which can be removed from the injected sites by exocytosis. In this study, injectable and implantable near-infrared (NIR) light-responsive microparticles are fabricated using droplet-based microfluidics. The particles are composed of 1-tetradecanol, as a class of non-toxic phase change material, and IR780, as a NIR-absorbing photothermal agent. Doxorubicin, an anticancer drug, is encapsulated in the particles to obtain NIR light-responsive anticancer drug carriers. The photothermal response of IR780 to NIR irradiation facilitates the release of the encapsulated drug through the melting of 1-tetradecanol and demonstrates the NIR light-responsive drug release. This study shows that IR780-encapsulated 1-tetradecanol microparticles fabricated by droplet-based microfluidics have great potential as injectable and implantable drug carriers featuring NIR light-sensitive drug release.

Amyloid-Based Injectable Hydrogel Derived from Hydrolyzed Hen Egg White Lysozyme.

Injectable hydrogels based on synthetic peptides have shown great promise in many biomedical applications. Yet, the high cost generally associated with synthetic peptides hinders the practical use of such peptide-based injectable hydrogel. To overcome this drawback, here, we propose to use the peptides from hydrolyzed low-cost natural protein as an economical and convenient peptide source to prepare an injectable hydrogel. We demonstrate the effectiveness of this alternative strategy using hen egg white lysozyme (HEWL) as an example. We used the peptide fragments from hydrolyzed HEWL as the gelator, and the magnesium ion as the performance enhancer to prepare the injectable hydrogel. We showed that the hydrogel is an amyloid gel as it was formed by a dense network of amyloid fibrils. We also showed that the hydrogel possesses a thixotropic property and displays a low cytotoxicity. The hydrolysis extent of HEWL was found to be a critical factor that influences the performance of the hydrogel. A fluorescence assay based on 8-anilinonaphthalene-1-sulfonic acid was proposed as a mean to precisely and conveniently control the hydrolysis extent of HEWL to enable the best injectability performance. At last, using doxorubicin as a model compound, we explored the potential of this amyloid-based hydrogel as an injectable drug carrier.

In situ photocrosslinked hyaluronic acid and poly (γ-glutamic acid) hydrogels as injectable drug carriers for load-bearing tissue application

Due to the syringeability of precursor solution and convenience of open surgical treatment, injectable hydrogels have gained growing attention in drug delivery application. For load-bearing tissue, the excellent mechanical property is an important requirement for delivery vehicles to resist external stress and loads. Herein, we prepared mechanically robust injectable hydrogels (HA/γ-PGA hydrogels for short) using methacrylate-functionalized hyaluronic acid and poly (γ-glutamic acid) via photopolymerization. The HA/γ-PGA hydrogels showed outstanding anti-compression ability and could suffer a more than 80% strain. Meanwhile, after 5 cycles of compression, HA/γ-PGA hydrogels could still recover quickly against external stress, showing excellent shape recovery capability. Moreover, the mechanical properties could be modulated easily by changing the molar ratio of HA to γ-PGA. The drug release behavior was also evaluated and the drug-loaded HA/γ-PGA hydrogels showed a weak burst release and sustained release behavior. Additionally, HA/γ-PGA hydrogels also exhibited superior biocompatibility. Therefore, HA/γ-PGA hydrogels have great potential as injectable drug carriers for load-bearing tissue application.

Studies on the preparation and controlled release of redox/pH-responsive zwitterionic nanoparticles based on poly-L-glutamic acid and cystamine

The enhancement of tumor intracellular drug uptake and resistance against nonspecific protein adsorption are essential for an injectable anticancer drug carrier. In the present study, a new type of redox/pH-responsive zwitterionic nanoparticles (NPs) was prepared using poly-L-glutamic acid and cystamine in aqueous solutions under mild conditions. The NPs showed surface charge convertible feature in response to pH change of the solutions. The NPs demonstrated excellent anti nonspecific protein adsorption. In vitro release profiles of the NPs, they showed redox/pH dual sensitivities in vitro release. The effective intracellular delivery behaviors were verified through investigation of cell viability, and confocal laser scanning microscopy observation of HeLa cells after incubation with the DOX-loaded NPs. The NPs were non-cytotoxic and would have potential applications as a drug delivery vehicle for enhancing intracellular uptake of anticancer drugs.

Hyperbranched polyglycerol-modified graphene oxide as an efficient drug carrier with good biocompatibility

As a promising drug carrier, graphene oxide (GO) has been studied widely in drug delivery due to its excellent loading ability to aromatic drugs. However, its biocompatibility, such as stability and blood compatibility, is now the biggest obstacle for its further application. Herein, the hyperbranched polyglycerol (HPG)-modified GO was prepared through the anionic ring-opening polymerization using GO as the initiator directly, and then the doxorubicin hydrochloride was loaded and showed obvious cytotoxicity to tumor cells. The obtained HPG-GO displayed good stability in the aqueous solution, as well showed low toxicity in vitro and in vivo. As an injectable drug carrier, HPG-GO showed good blood compatibility with negligible effect on the hemolysis and blood coagulation. Such a stable and blood-compatible GO derivative may be applied widely in drug delivery in the future.

Dual Drug Loaded Biodegradable Nanofibrous Microsphere for Improving Anti-Colon Cancer Activity.

One of the approaches being explored to increase antitumor activity of chemotherapeutics is to inject drug-loaded microspheres locally to specific anatomic sites, providing for a slow, long term release of a chemotherapeutic while minimizing systemic exposure. However, the used clinically drug carriers available at present have limitations, such as their low stability, renal clearance and residual surfactant. Here, we report docetaxel (DOC) and curcumin (CUR) loaded nanofibrous microspheres (DOC + CUR/nanofibrous microspheres), self-assembled from biodegradable PLA-PEO-PPO-PEO-PLA polymers as an injectable drug carrier without adding surfactant during the emulsification process. The obtained nanofibrous microspheres are composed entirely of nanofibers and have an open hole on the shell without the assistance of a template. It was shown that these DOC + CUR/nanofibrous microspheres could release curcumin and docetaxel slowly in vitro. The slow, sustained release of curcumin and docetaxel in vivo may help maintain local concentrations of active drug. The mechanism by which DOC + CUR/nanofibrous microspheres inhibit colorectal peritoneal carcinomatosis might involve increased induction of apoptosis in tumor cells and inhibition of tumor angiogenesis. In vitro and in vivo evaluations demonstrated efficacious synergistic antitumor effects against CT26 of curcumin and docetaxel combined nanofibrous microspheres. In conclusion, the dual drug loaded nanofibrous microspheres were considered potentially useful for treating abdominal metastases of colorectal cancer.