Drug Release System Research Articles

Hydrogels with Phosphate Groups as Potential Carriers of Bisphosphonates

Hydrogels are potential materials in many biomedical applications. A particularly promising application is their use in bone tissue engineering as implants or layers on the surface of titanium alloys. Disadvantage in the use of hydrogels in drug release system is often “burst release” effect what obstructs controlled release of pharmaceutically active agent. This functionality can be obtained by using an appropriate hydrogel, which has in its structure ions to which the drug is complexed. In this work, hydrogel materials containing mers with phosphate groups were prepared and used in the controlled drug release. The prepared material was functionalized with Ca2+, Mg2+, and Sr2+ ions. These ions were chosen because they support the osseointegration process. The possibility of sorption of the drug for osteoporosis (risedronate) was tested on the prepared hydrogels. Sorption was effective only on the hydrogel with calcium ions. The drug was evenly distributed throughout the hydrogel. The new hydrogel has proven to be able to retain the drug and slowly release it in small doses. We assume that the prepared material has the potential to be used as a coating for bone implants or as an implantable hydrogel for people suffering from osteoporosis.

The use of electrospinning in the development of systems for buccal drug delivery: a review

Electrospinning is a simple, low cost and versatile technology used for the manufacture of nanomaterials. The electrospun nanofibers produced are characterized by high porosity and large specific surface area, factors that make the membranes potentially useful in the development of systems for drug release. When it comes to drug release in the oral cavity, the nanofibers are highlighted due to the advantage of easy modulation of the drug release profile, by monitoring the morphology, porosity, chemical composition of the fibers and the electrospinning technique. In this sense, this study developed a literature review on the use of the electrospinning technique to obtain buccal drug delivery systems. Scientific articles published in the databases Science Direct and Embase were used, with the following descriptors and their combinations: [electrospinning] and [buccal drug delivery]. Articles published between 2013 and 2023 were considered. For the inclusion of the studies, the following criteria were used: articles published in English, experimental studies, and the descriptors should appear in the title, abstract, or keywords. Fourteen articles were included in the final analysis and from them it was verified the wide use of the electrospinning technique for the development of buccal drug delivery systems and the employment of active substances of various pharmacological classes. The analyzed studies conclude that the use of electro-spinning of drugs associated with other pharmaceutical excipients are promising tools in the development of drug delivery systems in the oral cavity, since they avoid first-pass hepatic metabolism, enzymatic degradation of the drug, present ease of administration and allow easy removal of the system in case of adverse events.

Development of a thermosensitive hydrogel based on Polaxamer 407 and gellan gum with inclusion complexes (Sulfobutylated-β-cyclodextrin–Farnesol) as a local drug delivery system

This work proposes the development of a thermosensitive local drug release system based on Polaxamer 407, also known as Pluronic® F-127 (PF-127), Gellan Gum (GG) and the inclusion complex Sulfobutylated-β-cyclodextrin (CD) with Farnesol (FOH). Rheological properties of the hydrogels and their degradation were studied. According to the rheological results, a solution of 20% w/v of PF-127 forms a strong gel with a gelling temperature of about 25 °C (storage modulus of 15,000 Pa). The addition of the GG increased the storage modulus (optimal concentration of 0.5 % w/v) twofold without modifying the gelling temperature. Moreover, including 0.5% w/v of GG also increased 6 times the degradation time of the hydrogel. Regarding the inclusion complex, the addition of free CD decreased the viscosity and the gel strength since polymer chains were included in CD cavity without affecting the gelling temperature. Contrarily, the inclusion complex CD-FOH did not significantly modify any property of the formulation because the FOH was hosted in the CD. Furthermore, a mathematical model was developed to adjust the degradation time. This model highlights that the addition of the GG decreases the number of released chains from the polymeric network (which coincides with an increase in the storage modulus) and that the free CD reduces the degradation rate, protecting the polymeric chains. Finally, FOH release was quantified with a specific device, that was designed and printed for this type of system, observing a sustainable drug release (similar to FOH aqueous solubility, 8 μM) dependent on polymer degradation.

MiRNA320a Inhibitor-Loaded PLGA-PLL-PEG Nanoparticles Contribute to Bone Regeneration in Trauma-Induced Osteonecrosis Model of the Femoral Head.

This study aimed to explore the effect of a nanomaterial-based miR-320a inhibitor sustained release system in trauma-induced osteonecrosis of the femoral head (TIONFH). The miR-320a inhibitor-loaded polyethylene glycol (PEG)- Poly(lactic-co-glycolic acid) (PLGA)- Poly-L-lysine (PLL) nanoparticles were constructed using the double emulsion method. The TIONFH rabbit model was established to observe the effects of miR-320a inhibitor nanoparticles in vivo. Hematoxylin-eosin staining and microcomputed tomography scanning were used for bone morphology analysis. Bone marrow mesenchymal stem cells (BMSCs), derived from TIONFH rabbits, were used for in vitro experiments. Cell viability was determined using the MTT assay. High expression of miR-320a inhibited the osteogenic differentiation capacity of BMSCs in vitro by inhibiting the expression of the osteoblastic differentiation markers ALP and RUNX2. MiR-320a inhibitor-loaded PEG-PLGA-PLL nanoparticles were constructed with a mean loading efficiency of 1.414 ± 0.160%, and a mean encapsulation efficiency of 93.45 ± 1.24%, which released 50% of the loaded miR-320a inhibitor at day 12 and 80% on day 18. Then, inhibitor release entered the plateau. After treatment with the miR-320a inhibitor nanoparticle, the empty lacunae were decreased in the femoral head tissue of TIONFH rabbits, and the osteoblast surface/bone surface (Ob.S/BS), osteoblast number/bone perimeter (Ob.N/B.Pm), bone volume fraction, and bone mineral density increased. Additionally, the expression of osteogenic markers RUNX2 and ALP was significantly elevated in the TIONFH rabbit model. The miR-320a inhibitor-loaded PEG-PLGA-PLL nanoparticle sustained drug release system significantly contributed to bone regeneration in the TIONFH rabbit model, which might be a promising strategy for the treatment of TIONFH.

Genotype-specific precision tumor therapy using mitochondrial DNA mutation-induced drug release system.

Precise killing of tumor cells without affecting surrounding normal cells is a challenge. Mitochondrial DNA (mtDNA) mutations, a common genetic variant in cancer, can directly affect metabolic homeostasis, serving as an ideal regulatory switch for precise tumor therapy. Here, we designed a mutation-induced drug release system (MIDRS), using the single-nucleotide variation (SNV) recognition ability and trans-cleavage activity of Cas12a to convert tumor-specific mtDNA mutations into a regulatory switch for intracellular drug release, realizing precise tumor cell killing. Using Ce6 as a model drug, MIDRS enabled organelle-level photodynamic therapy, triggering innate and adaptive immunity simultaneously. In vivo evaluation showed that MIDRSMT could identify tumor tissue carrying SNVs in mtDNA in unilateral, bilateral, and heterogeneous tumor models, producing an excellent antitumor effect (~82.6%) without affecting normal cells and thus resulting in a stronger systemic antitumor immune response. Additionally, MIDRS was suitable for genotype-specific precision drug release of chemotherapeutic drugs. This strategy holds promise for mutation-specific personalized tumor treatment approaches.

Future Opportunities in the Field of Drug Delivery Research

Much of the priorities in drug delivery research are focused on targeted drug delivery for cancer therapies and a wide range of controlled drug release systems for commonly used active pharmaceutical ingredients (APIs). In this “thousand words article” we highlight some of the emerging health threats and future opportunities for drug delivery research. Important emerging health threats include viral pandemics beyond COVID, antibiotic-resistant pathogens, the need for new antifungal therapies, and emerging diseases caused by increasing pollution and climate change. Fundamentally new drugs may be needed. For example, one little known research effort focuses on the development of new antibiotics based on metal-organic frameworks. Finally, new delivery approaches will be needed. This is illustrated by the development of a topical peptide delivery system as a wound dressing for burn patients, combining biotechnology (a new peptide) with polymer science (a new topical delivery system) to address a medical need (burn injury) for which there is currently no effective treatment. Another important trend is the shift in our collective understanding of impact, moving away from “counting papers” to considering the societal benefit of the research including its potential for commercialization. To remain relevant in the coming decade, we need to anticipate and embrace future challenges. This is particularly important for younger scientists.

Injectable hyperbranched PEG crosslinked hyaluronan hydrogel microparticles containing mir-99a-3p modified subcutaneous ADSCs-derived exosomes was beneficial for long-term treatment of osteoarthritis

Exosomes (Exos) secreted by adipose-derived stem cells (ADSCs) have shown potential in alleviating osteoarthritis (OA). Previous studies indicated that infrapatellar fat pad (IPFP) derived stem cells (IPFSCs) may be more suitable for the treatment of OA than subcutaneous adipose tissue (ScAT) derived stem cells (ScASCs). However, it remains unclear which type of Exos offers superior therapeutic benefit for OA. This study first compared the differences between Exos derived from IPFP stem cells (ExosIPFP) and ScAT stem cells (ExosScAT) in OA treatment. Results suggested that ExosIPFP significantly inhibit the degradation of cartilage extracellular matrix (ECM) than ExosScAT, following this, the differences in microRNA (miRNA) expression between the two types of Exos using small RNA sequencing were performed. Subsequently, miR-99 b-3p was chosen and over-expressed in ExosScAT (ExosScAT−99b−3p), both in vivo and in vitro experiments demonstrated its efficacy in inhibiting the expression of ADAMTS4, promoting the repair of the ECM in OA. Finally, microfluidic technology was performed to fabricate a hyaluronan-based hydrogel microparticles (HMPs) for encapsulating Exos (HMPs@exos), the injectability, sustained release of Exos and long-term therapeutic effect on OA were validated. In summary, these results suggest miR-99 b-3p regulates the degradation of cartilage ECM by targeting ADAMTS4, the upregulation of miR-99 b-3p in ExosScAT would enable them to exhibit comparable or even superior effectiveness to ExosIPFP for OA treatment, making it a promising approach for OA treatment. Considering the abundant resources of ScAT and the limited availability of IPFP, ScAT harvested through liposuction could be genetically engineered to yield Exos for OA treatment. Furthermore, the encapsulation of Exos in HMPs provides an injectable sustained local drug release system, which could potentially enhance the efficacy of Exos and hold potential as future therapeutic strategies.

Mechanistic Computational Modeling of Implantable, Bioresorbable Drug Release Systems.

Implantable, bioresorbable drug delivery systems offer an alternative to current drug administration techniques; allowing for patient-tailored drug dosage, while also increasing patient compliance. Mechanistic mathematical modeling allows for the acceleration of the design of the release systems, and for prediction of physical anomalies that are not intuitive and may otherwise elude discovery. This study investigates short-term drug release as a function of water-mediated polymer phase inversion into a solid depot within hours to days, as well as long-term hydrolysis-mediated degradation and erosion of the implant over the next few weeks. Finite difference methods are used to model spatial and temporal changes in polymer phase inversion, solidification, and hydrolysis. Modeling reveals the impact of non-uniform drug distribution, production and transport of H+ ions, and localized polymer degradation on the diffusion of water, drug, and hydrolyzed polymer byproducts. Compared to experimental data, the computational model accurately predicts the drug release during the solidification of implants over days and drug release profiles over weeks from microspheres and implants. This work offers new insight into the impact of various parameters on drug release profiles, and is a new tool to accelerate the design process for release systems to meet a patient specific clinical need.

In situ synthesis of UV-responsive mesoporous SiO2 drug release systems using the associates of anionic drugs and cationic silica source as templates

In situ synthesis of UV-responsive mesoporous SiO2 drug release systems using the associates of anionic drugs and cationic silica source as templates

Preparation of a controlled drug release system from semi-interpenetrating polymeric network hydrogel of NaAlg-g-poly(NaA)/PVP

Preparation of a controlled drug release system from semi-interpenetrating polymeric network hydrogel of NaAlg-g-poly(NaA)/PVP

Polyurethane-based nanofibrous mat containing porphyrin with photosensitivity and bactericidal properties can promote cutaneous tissue healing in rats

The regeneration of cutaneous tissue is one of the most challenging issues in human regenerative medicine. To date, several studies have been done to promote cutaneous tissue healing with minimum side effects. The healing potential of polyurethane (PU)/Poly (caprolactone)–poly (ethylene glycol)–poly (caprolactone) (PCEC)/chitosan (CS) (PCS) nanofibrous mat with cationic photosensitizer meso tetrakis (N-methyl pyridinium-4-yl) porphyrin tetratosylate salt (TMP) was examined. The CS tripolyphosphate nanoparticles (CSNPs) were prepared and loaded by TMP to provide an efficient drug release system (TMPNPs) for delivery of TMP to promote wound healing. In in vitro setting, parameters such as bactericidal effects, cytocompatibility, and hemolytic effects were examined. The healing potential of prepared nanofibrous mats was investigated in a rat model of full-thickness cutaneous injury. PCS/TMP/TMPNPs nanofibers can efficiently release porphyrin in the aqueous phase. The addition of TMPNPs and CS to the PU backbone increased the hydrophilicity, degradation, and reduced mechanical properties. The culture of human fetal foreskin fibroblasts (HFFF2) on PCS/TMP/TMPNPs scaffold led to an increased survival rate and morphological adaptation analyzed by MTT and SEM images. Irradiation with a red laser (635 nm, 3 J/cm2) for the 30 s reduced viability of S. aureus and E. Coli bacteria plated on PCS/TMP and PCS/TMP/TMPNPs nanofibrous mats compared to PU/PCEC (PC) and PU/PCEC/CS (PCS) groups, indicating prominent antibacterial effects of PCS/TMP and PCS/TMP/TMPNPs nanofibrous (p < 0.05). Data indicated that PCS/TMP/TMPNPs mat enhanced healing of the full-thickness excisional wound in a rat model by the reduction of inflammatory response and fibrotic changes compared to the PC, and PCS groups (p < 0.05). Immunofluorescence imaging indicated that levels of Desmoglein were increased in rats that received PCS/TMP/TMPNPs compared to the other groups. It is found that a PU-based nanofibrous mat is an appropriate scaffold to accelerate the healing of injured skin.Graphical abstract

Intravitreal implants manufactured by supercritical foaming for treating retinal diseases

Chronic retinal diseases, such as age-related macular degeneration (AMD), are a major cause of global visual impairment. However, current treatment methods involving repetitive intravitreal injections pose financial and health burdens for patients. The development of controlled drug release systems, particularly for biological drugs, is still an unmet need in prolonging drug release within the vitreous chamber. To address this, green supercritical carbon dioxide (scCO2) foaming technology was employed to manufacture porous poly(lactic-co-glycolic acid) (PLGA)-based intravitreal implants loaded with dexamethasone. The desired implant dimensions were achieved through 3D printing of customised moulds. By varying the depressurisation rates during the foaming process, implants with different porosities and dexamethasone release rates were successfully obtained. These implants demonstrated controlled drug release for up to four months, surpassing the performance of previously developed implants. In view of the positive results obtained, a pilot study was conducted using the monoclonal antibody bevacizumab to explore the feasibility of this technology for preparing intraocular implants loaded with biologic drug molecules. Overall, this study presents a greener and more sustainable alternative to conventional implant manufacturing techniques, particularly suited for drugs that are susceptible to degradation under harsh conditions.

Potential use of liposomes in tuberculosis treatment

Tuberculosis is among the infectious diseases with the highest mortality and morbidity worldwide, behind the COVID-19 pandemic. It can affect any organ, although the respiratory infection is the most common. The correct activation of the immune response eliminates or contain the bacteria; however, the active disease is progressive and must be treated under strict supervision. Treatment for tuberculosis is prolonged and consists of a combination of several antibiotics associated with a wide variety of adverse effects. These effects are the main cause of therapeutic abandonment, which facilitates the appearance of drug-resistant strains. Hence the importance of developing new therapeutic strategies to reduce the dose of the drug or its administration time. To achieve these objectives, the use of nano-vehicles, which are controlled and directed drug release systems, has been proposed. Specifically, liposomes are formulations that have advantages when administered by the respiratory route since they facilitate the reach of the respiratory mucosa and the lungs, which are the main organs affected by tuberculosis. This review analyzes the use of nano-vehicles as effective drug delivery systems and the formulations under study. Perspectives for the application of nanotechnology in the development of new pharmacological treatments for tuberculosis are also proposed.

Combining emulsion electrospinning with surface functionalization to fabricate multistructural PLA/CS@ZIF-8 nanofiber membranes toward pH-responsive dual drug delivery

Developing of the multifunctional polymeric carrier for controlled drug release is still one of most challenging task. In this work, a pH-responsive dual drug delivery system was designed and prepared based on the zeolitic imidazolate framework-8 (ZIF-8). The poly(lactic acid)/chitosan (PLA/CS) core-shell nanofiber membranes by emulsion electrospinning, which the hydrophilic drug (Astragalus Polysacharin, APS) was encapsulated in the CS core and the hydrophobic drug (Camptothecin, CPT) was loaded into the PLA shell, respectively. Subsequently, ZIF-8 nanoparticles served as the protective layer were immobilized on the surface of PLA/CS to form multi-structural PLA/CS@ZIF-8 nanofiber membranes. In vitro drug release of nanofiber membranes were studied in the acidic and neutral medium, respectively. The results were that the hydrophilicity and surface roughness of nanofiber membranes rose with increasing of 2-MIM concentrations. The nanofiber membranes also had excellent pH-responsive and controlled release property. Furthermore, the drug release of PLA/CS@ZIF-8 for either APS or CPT were all carried out in a coexisting manner of diffusion and skeleton corrosion. In addition, in vitro cytotoxicity assay indicated nanofiber membranes with good cytocompatibility. Therefore, the multi-structured PLA/CS@ZIF-8 nanofiber membranes has been used as a potential pH-responsive dual drug release system.

Novel chitosan/γ-alumina/carbon quantum dot hydrogel nanocarrier for targeted drug delivery

Curcumin (CUR) is among the most natural and effective antitumor drugs for cancer treatment. These drugs have low solubility and short half-lives that reduce their effectiveness in drug release systems. Herein, a hydrogel nanocarrier containing chitosan (CS), alumina (γ-Al2O3), and carbon quantum dots (CQDs) was prepared by the water-in-oil-in-water (W/O/W) double nanoemulsion method. DLS revealed a nanocarrier size of 227 nm, with a zeta potential of −37.8 mV, which corroborates its stability. FE-SEM showed its quasi-spherical shape, FT-IR and XRD confirmed the presence of all the components in the nanocomposite and gave information about the intermolecular interactions between them and the crystalline nature of the nanocarrier, respectively. The drug loading (48 %) and entrapment efficiency (86 %) were higher than those reported previously for other CUR nanocarriers. The drug release profile revealed a controlled and stable release, and a pH-sensitive behavior, with faster CUR release in an acid environment. The breast cancer cell line was examined by cytotoxicity and cell apoptosis analyses. The results showed that the slow release over time and the programmed cell death were due to interactions between CUR and the nanocarrier. Considering the results obtained herein, CS/γAl2O3/CQDs/CUR can be considered as a promising new nanosystem for tumor treatment.

Matrix Metalloproteinase-Responsive Drug Delivery Systems.

Matrix metalloproteinases (MMPs) are a class of endopeptidases that are dependent on zinc and facilitate the degradation of extracellular matrix (ECM) proteins, thereby playing pivotal parts in human physiology and pathology. MMPs regulate normal tissue and cellular functions, including tissue development, remodeling, angiogenesis, bone formation, and wound healing. Several diseases, including cancer, inflammation, cardiovascular diseases, and nervous system disorders, have been linked to dysregulated expression of specific MMP subtypes, which can promote tumor progression, metastasis, and inflammation. Various MMP-responsive drug delivery and release systems have been developed by harnessing cleavage activities and overexpression of MMPs in affected regions. Herein, we review the structure, substrates, and physiological and pathological functions of various MMPs and highlight the strategies for designing MMP-responsive nanoparticles to improve the targeting efficiency, penetration, and protection of therapeutic payloads.

Self‐trigger and on‐demand drug delivery system based on TiO2 nanotube arrays and its drug release behaviour

AbstractThe foundation of drug delivery systems based on titanium dioxide nanotube arrays has become an important means to increase the drug release performance of bone implantation materials. However, most of the conventional platforms have some disadvantages, such as large sudden release, uncontrollable, unintelligent, or not on‐demand drug release process. Herein, the authors develop a unique self‐triggering drug release system (SDDS), utilizing the advantages of 1‐Tetradecanol (TD), such as decent biocompatibility, a phase transition temperature of 37.8°C, and the inexistence of complex chemical reaction process. The establishment of the platform can make a large amount of the anti‐inflammatory drug (ibuprofen, IBU) released when the body or the affected area is inflamed, that is, when the temperature rises. Conversely, only a small amount or no drug is released when there is no inflammation, thereby achieving self‐trigger release and on‐demand release. The experimental results show that the system combines good self‐trigger release properties, release sensitivity, drug release cycle, and low selectivity to the loaded drugs.

3D bioprinting for diagnostic and therapeutic application

Application 3D printing technology in medical diagnosis and therapeutics had revolutionaries the health care sector. 3 D bioprinting based on additive manufacturing process which helps in development of smart, low cost, precise, patient specific medical solution. It deals from designing and development of artificial implants, orthotic, prosthetics to development of wound healing dressing material, mems-based biosensors arrays that could be used for diagnostic and therapeutic applications. Advances in 3D printing methods could help in synthesizing precise drug to its nano size and development of smart controlled patient specific drug release system. 3D bioprinting from macro scale to nanoscale involves the method known as solid free form fabrication in combination of bio-ink or biomaterials. The development of patient specific 3D model done from medical images like Computer Tomography (CT) and Medical Resonance imaging (MRI) and its analysis is done on commercially available simulating software. In this paper the detailed latest applications and methods of 3D bioprinting in various emerging diagnostic and therapeutic techniques was discussed.

A short review on the applicability and use of cubosomes as nanocarriers.

Cubosomes are nanostructured lipid-based particles that have gained significant attention in the field of drug delivery and nanomedicine. These unique structures consist of a three-dimensional cubic lattice formed by the self-assembly of lipid molecules. The lipids used to construct cubosomes are typically nonionic surfactants, such as monoolein, which possess both hydrophilic and hydrophobic regions, allowing them to form stable, water-dispersible nanoparticles. One of the key advantages of cubosomes is their ability to encapsulate and deliver hydrophobic as well as hydrophilic drugs. The hydrophobic regions of the lipid bilayers provide an ideal environment for incorporating lipophilic drugs, while the hydrophilic regions can encapsulate water-soluble drugs. This versatility makes cubosomes suitable for delivering a wide range of therapeutic agents, including small molecules, proteins, peptides, and nucleic acids. The unique structure of cubosomes also offers stability and controlled release benefits. The lipid bilayers provide a protective barrier, shielding the encapsulated drugs from degradation and improving their stability. Moreover, the cubic lattice arrangement enables the modulation of drug release kinetics by varying the lipid composition and surface modifications. This allows for the development of sustained or triggered drug release systems, enhancing therapeutic efficacy and reducing side effects. Furthermore, cubosomes can be easily modified with targeting ligands or surface modifications to achieve site-specific drug delivery, enhancing therapeutic selectivity and reducing off-target effects. In conclusion, cubosomes offer a versatile and promising platform for the delivery of therapeutic agents. In this manuscript, we will highlight some of these applications.

Preparation of β-Cyclodextrin Conjugated, Gelatin Stabilized SBA 15-CuInS2/ZnS Quantum Dot Nanocomposites for Camptothecin Release

Camptothecin (CPT) is a potential anticancer drug. However, it faces challenges due to its poor water solubility and the need for an efficient drug release system. Herein, we developed a novel system composed of gelatin stabilized, mesoporous silica SBA15 encapsulated CuInS2/ZnS (CIS/ZnS) quantum dots (QDs) conjugated with β-cyclodextrin (β-CDs) for its potential use in the release of CPT. In this multifunctional system, β-CDs served as the drug carrier, SBA15 encapsulated QDs is capable of imaging and the gelatin was used to enhance the carrier-drug interaction. Fourier transform infrared (FTIR) analysis confirmed the successful conjugation of β-CDs to the Gel-SBA15 CIS/ZnS QDs, while optical analyses revealed excellent emission properties and high photostability. The β-CD-conjugated Gel-SBA15-CIS/ZnS QD nanocomposite was used to obtain the soluble derivate of CPT which further demonstrated a drug release profile following the triphasic model. Overall, the improved photostability and acceptable drug release profile of the β-CD conjugated Gel-SBA15-CIS/ZnS QD nanocomposite hold great promise for both imaging and therapeutic applications.Graphical