Local Drug Release Research Articles

In situ forming and self-crosslinkable protein hydrogels for localized cancer therapy and topical wound healing.

Proteins, inherently biocompatible and biodegradable, face a challenge in forming stable hydrogels without external chemical crosslinkers. Here, we construct a ring-shaped trimeric SpyTag-fused Proliferating Cell Nuclear Antigen Protein (ST-PCNA) as a core protein building block, and a dumbbell-shaped tandem dimeric SpyCatcher (SC-SC) as a bridging component. Self-crosslinked PCNA/SC-SC Protein (2SP) hydrogels are successfully formed by simply mixing the solutions of ST-PCNA and SC-SC, without chemical crosslinkers. During their formation by mixing, various cargo molecules, including anti-cancer drugs, photosensitizers, and functional proteins, are efficiently incorporated, producing cargo@2SP hydrogels. Most of the entrapped cargo molecules gradually release as the hydrogels erode. Anti-cancer drug- or photosensitizer-incorporated 2SP hydrogels are successfully formed through localized injection beneath the 4T1 tumor in mice. The localized gradual release of drugs in physiological microenvironment substantially suppresses tumor growth, and highly localized photosensitizers retained in the 2SP hydrogels raises the local temperature above 45°C upon laser irradiation, resulting in a significant suppression of tumor growth. Additionally, the topical administration of growth factor proteins-incorporated 2SP hydrogels to the incision wound area effectively regenerates the skin, with rapid reconstruction of extracellular matrix. The injectable and self-crosslinkable 2SP hydrogels developed here offer promise as novel biocompatible scaffolds for local therapy.

Thymoquinone-loaded Nanosized Ethosomal-based Hydrogels: Their Preparation, Characterization, in Vitro, Ex Vivo, and Antimicrobial Evaluation against Staphylococcus aureus.

Thymoquinone (TQ) is found in the seeds of Nigella sativa. It has immunomodulatory, antibacterial, anti-inflammatory, antioxidant, astringent, antifungal, and antihistaminic properties, making it a highly valuable compound of interest. However, the use of it as a therapeutic drug is highly challenging because of its poor solubility, low bioavailability, and short-term stability. The present study focused on a nanosized ethosome formulation of thymoquinone with potent antimicrobial activity against Staphylococcus aureus. This study aimed to develop nanosized TQ-loaded ethosome-based hydrogels and evaluate their antimicrobial effects. The methods included UV‒VIS spectrophotometer analysis, solubility studies, preparation of TQ-loaded ethosomes, thermodynamic stability, in vitro drug release, characterization, preparation of ethosome- based hydrogels, ex vivo skin permeation, skin drug retention, and antimicrobial studies against S. aureus. UV‒VIS analysis revealed that thymoquinone (TQ) demonstrated a maximum absorbance peak at λmax 254 nm. TQ has the highest solubility in ethanol (60 mg/mL) and soy lecithin (65 mg/mL). TQ solubility in PBS 7.4 (75 mg/mL) with ethanol (50:50% w/v) was found to be crucial for determining in vitro and ex vivo drug release. Ethosomes were developed using soy lecithin (1.5-4.5% w/w), cholesterol (0.20-0.42% w/w), and ethanol (30-47% w/w) across ten formulations (E1-E10). These ethosomes were further evaluated for physical stability. Formulations E6-E10, with optimal concentrations of soy lecithin, cholesterol, and high ethanol, showed thermodynamic stability for up to 6 weeks. These materials were selected for further study because of their stability and in vitro drug release. E6 resulted in the greatest drug release and permeation due to the optimal lipid, cholesterol, and higher ethanol concentrations. E6, with a particle size of 114.8 nm, a PDI of 0.247, and a zeta potential of -0.497 mV, showed optimal stability and drug encapsulation, and the TEM results confirmed the presence of spherical vesicles. The addition of carbopol-940 (1% w/w) resulted in the formation of a gel, enhancing the topical application and sustained release of the drug. Compared with the TQCG hydrogel, the E6 hydrogel showed superior TQ permeation and flux over 24 hours. The first-order model fits the release kinetics, confirming the suitability of the E6 hydrogel for further study. The E6 hydrogel retained 3.6 times more drugs than TQ-CG, enhancing skin penetration and drug delivery. The TQ-loaded ethosome (E6 in D3) demonstrated the second-highest antimicrobial action, followed by the E6 hydrogel [D2], with the Clinsol gel as a control [C] showing the maximum inhibition against S. aureus. The efficacy of E6 is likely due to better diffusion. The slower diffusion of the hydrogel provides sustained action, making it effective for prolonged topical drug delivery. The E6 hydrogel shows promise for local therapeutic benefits and sustained drug release and could be a superior herbal option for managing skin infections.

Disease‐Adaptive Drug Delivery to the Inflamed Intestinal Mucosa Using Poly(Lactic‐Co‐Glycolic Acid)‐cyclodextrin Hybrid Nanocarriers

AbstractFluctuating severity of symptoms is a common hallmark of many inflammatory disorders, including inflammatory bowel disease (IBD). Addressing the pH changes during active and resting phases in IBD‐affected tissue, a disease‐adaptive nanocarrier system is designed for oral administration, enabling pH‐dependent local drug release. The hybrid carrier combines poly(lactic‐co‐glycolic acid) and an amphiphilic cyclodextrin derivative, with physicochemical properties and drug release kinetics controlled by adjusting polymer ratios. The systems exhibited baseline drug release at pH 5 with increased rates at pH 2, which is characteristic of actively inflamed IBD tissue. Assessing the impact of biomolecule adhesion, biocorona formation was studied using ex vivo human intestinal fluids. Corona composition highly depended on the patient's prandial state and the nanocarrier matrix, with proteins predominating in the fasted state and lipids in the fed state. Notably, differences in the attachment of proteins and free fatty acids are detected in the latter. Transport studies using human in vitro models of the inflamed intestine revealed mucosal accumulation, facilitating localized drug delivery and effectively reducing cytokine levels to basal concentrations. This hybrid system highlights the potential of disease‐adaptive drug release for inflammatory disease treatment and underscores the impact of biocorona formation on therapeutic performance in the gastrointestinal tract.

Inhalable Chemotactic Liposome for Targeted Modulation of Pulmonary Pre‐Metastatic Niche

AbstractInhalation offers a non‐invasive method to administer drugs to lungs, but achieving selective delivery to pulmonary lesions while sparing normal lung tissues remains challenging. Here, the development of an inhalable chemotactic liposome designed for targeted modulation of pulmonary pre‐metastatic niche (PMN) is reported. The inhaled liposome can migrate along chemokine gradients, preferentially accumulating in chemokine‐secreting PMNs within the lung. Upon localized drug release, the liposome mitigates fibrosis, and disrupts PMN evolution, thereby attenuating the pro‐metastatic role of PMN as a hospitable “soil” for residual tumor cell “seeding” post‐surgery. This approach further complements a sprayable hydrogel developed for immediate post‐surgical application within the tumor resection cavity. While this hydrogel alone reduces the metastatic potential of postoperative tumor residues, it proves insufficient in halting the spread to lungs. However, the integration of the inhalable liposome and sprayable hydrogel into a dual‐pronged strategy presents a patient‐friendly method that simultaneously targets both the pro‐metastatic PMN “soil” and metastatic tumor “seeds”, resulting in significant inhibition of postoperative lung metastasis.

Polysaccharide-based drug delivery targeted approach for colon cancer treatment: A comprehensive review.

Colon cancer is a leading cause of cancer-related morbidity and mortality worldwide, necessitating advancements in therapeutic strategies to improve outcomes. Current treatment modalities, including surgery, chemotherapy, and radiation, are limited by systemic toxicity, low drug utilization rates, and off-target effects. Colon-targeted drug delivery systems (CDDS) offer a promising alternative by leveraging the colon's unique physiology, such as near-neutral pH and extended transit time, to achieve localized and controlled drug release. Polysaccharide-based CDDS, utilizing natural polymers like chitosan, cyclodextrin, pectin, guar gum, alginate, hyaluronic acid, dextran, chondroitin sulfate, and inulin, have emerged as innovative approaches for improving the specificity and efficacy of colon cancer treatments. These biocompatible and biodegradable polymers enable site-specific drug delivery, enhance tumor apoptosis, reduce systemic side effects, and improve patient compliance. This review evaluates recent advancements in polysaccharide-based CDDS, detailing their drug release mechanisms, therapeutic potential, and challenges in overcoming gastrointestinal transit and pH variability. Studies highlight the successful formulation of nanoparticles, microspheres, and other delivery systems, demonstrating targeted drug delivery, improved bioavailability, and enhanced cytotoxicity against colon cancer cells in-vitro and in-vivo. The review underscores the need for continued research on polysaccharide-based CDDS for colon cancer treatment, offering a path toward more effective, patient-centered oncological care.

Therapeutic Potential of Microneedle Assisted Drug Delivery for Wound Healing: Current State of the Art, Challenges, and Future Perspective.

Microneedles (MNs) appear as a transformative and minimally invasive platform for transdermal drug delivery, representing a highly promising strategy in wound healing therapeutics. This technology, entailing the fabrication of micron-scale needle arrays, enables the targeted and efficient delivery of bioactive agents into the epidermal and dermal layers without inducing significant pain or discomfort. The precise penetration of MNs facilitates localized and sustained drug release, which significantly enhances tissue regeneration and accelerates wound closure. Furthermore, MNs can be engineered to encapsulate essential bioactive compounds, including antimicrobial agents, growth factors, and stem cells, which are critical for modulating the wound healing cascade and mitigating infection risk. The biodegradable nature of these MNs obviates the need for device removal, rendering them particularly advantageous in the management of chronic wounds such as diabetic ulcers and pressure sores. The integration of nanotechnology within MNs further augments their drug-loading capacity, stability, and controlled-release kinetics, offering a sophisticated therapeutic modality. This cutting-edge approach has the potential to redefine wound care by optimizing therapeutic efficacy, reducing adverse effects, and enhancing patient adherence. As MN technology advances, its application in wound healing exemplifies a dynamic frontier within biomedical engineering and regenerative medicine.

A versatile two-light mode triggered system for highly localized sequential release of reactive oxygen species and conjugated drugs from mesoporous organosilica particles.

The increasing prevalence of antimicrobial resistance and adverse effects of systemic treatments calls for urgent reevaluation of current methods that rely on excessive, uncontrolled drug administration. In recent years triggerable systems have emerged as promising alternatives, enabling time-controlled and localized drug release, which are only activated if necessary. Light is an obvious candidate as an external trigger, since it allows for localized activation, is non-invasive and its wavelength and intensity can be tailored to fit the demands of the drug release system. Such localized and triggered systems minimize off-target effects and undesired exposure, making it a promising tool for combating health threats such as antimicrobial resistance. However, the limited tissue penetration of visible light significantly limits the applicability of this concept in vivo. Here, we introduce an innovative triggerable drug release system, based on mono-, bi-, and tri-functionalized mesoporous organosilica particles (MOPs). The limited tissue penetration is addressed by an advanced trigger system featuring two-photon absorption. Two-photon absorption enables utilization of near-infrared (NIR) light as a trigger, which is known to exhibit an enhanced penetration depth. The particles are designed to release reactive oxygen species (ROS) upon NIR irradiation and undergo Förster resonance energy transfer (FRET) to a ROS producing dye. Moreover, by oxidative cleavage, an additional therapeutic agent is released in a cascade reaction, enhancing the system's effectiveness. The ROS release is microscopically demonstrated in situ and, for the first time, release of a fluorescent compound (therapeutic agent) in a cascade reaction is observed in real-time, providing valuable insights into the behavior and performance of our particles. This novel sequential dual-release platform for light-triggered therapeutic delivery has great potential for advanced therapeutic applications in both superficial and deep tissue treatments.

Optically Controlled Drug Delivery Through Microscale Brain-Machine Interfaces Using Integrated Upconverting Nanoparticles.

The aim of this work is to incorporate lanthanide-cored upconversion nanoparticles (UCNP) into the surface of microengineered biomedical implants to create a spatially controlled and optically releasable model drug delivery device in an integrated fashion. Our approach enables silicone-based microelectrocorticography (ECoG) implants holding platinum/iridium recording sites to serve as a stable host of UCNPs. Nanoparticles excitable in the near-infrared (lower energy) regime and emitting visible (higher energy) light are utilized in a study. With the upconverted higher energy photons, we demonstrate the induction of photochemical (cleaving) reactions that enable the local release of specific dyes as a model system near the implant. The modified ECoG electrodes can be implanted in brain tissue to act as an uncaging system that releases small amounts of substance while simultaneously measuring the evoked neural response upon light activation. In this paper, several technological challenges like the surface modification of UCNPs, the immobilization of particles on the implantable platform, and measuring the stability of integrated UCNPs in in vitro and in vivo conditions are addressed in detail. Besides the chemical, mechanical, and optical characterization of the ready-to-use devices, the effect of nanoparticles on the original electrophysiological function is also evaluated. The results confirm that silicone-based brain-machine interfaces can be efficiently complemented with UCNPs to facilitate local model drug release.

Hydroxyl Functionalization of a Titanium Implant Drug Carrier Channel Modified by Vacuum Drying-Assisted Laser Texturing to Achieve Delayed Release of CIP-PLGA Microsphere Suspension.

Titanium alloys are commonly used for bone grafting, but in mandibular defect repair, implantation possibly fails due to bacterial infection. The establishment of a long-acting drug delivery system through microspheres and titanium channels can reduce the risk of infection. However, there is insufficient research on the mechanism of microsphere attachment and microsphere-liquid two-phase flow in the hydroxyl-functionalized titanium implantation channel modified by a vacuum-drying-assisted laser texturing. In this paper, poly(lactic-co-glycolic acid) (PLGA) loaded with ciprofloxacin (CIP) was attached to the titanium channel by vacuum drying-assisted laser texturing. Titanium macroscopic flow channels and microscopic texture morphology were designed; three mathematical models of titanium substrate-microsphere-droplet interactions were developed, and the hydroxyl-based surface functionalization mechanism and the effect of laser texture parameters on microsphere adhesion and microsphere-liquid two-phase flow on titanium channels were investigated. The results showed that vacuum drying-assisted laser texture can control the bonding degree of the PLGA hydroxyl group to the titanium channel, which affects the adhesion of microspheres. The laser texture modification can control the flow rate of the microsphere suspension in the titanium channel to achieve a dynamic adjustment of the release effect. The CIP-PLGA microsphere drug delivery system, based on vacuum drying-assisted laser texturing, enables sustained local drug release, providing a potential strategy to suppress inflammation around the implant and reduce the risk of postoperative infection.

Effect of Gentamicin-Loaded Calcium Phosphate Coating and Polymeric Coating on the Degradation Properties of Biodegradable Iron-Based Biomaterials.

In the past decades, iron has been one of the intensively studied biodegradable metals due to its suitable mechanical properties, but it suffers from slow degradation in a physiological environment and low bioactivity. In this work, the beneficial properties of ceramic and polymer coatings were merged to enhance the corrosion properties and biological compatibility of Fe-based biomaterials. A new bilayer coating for Fe-based biomaterials that speeds up degradation while offering controlled, localized drug release to prevent infections was prepared. In addition, bioactive coatings with an incorporated antibiotic (gentamicin, Ge) were produced to introduce antibacterial properties into the prepared biomaterials and thus increase their bioactivity. The calcium phosphate (CaP) coating layer as well as a bioactive coating layer of CaP doped with gentamicin was electrochemically deposited onto an iron substrate. A layer of poly(ethylene glycol) was subsequently applied to the selection of prepared specimens to create a bilayer ceramic/polymer coating. Electrochemical and immersion corrosion tests revealed that the application of a bilayer coating allowed achieving the desired acceleration of degradation, while the application of only a ceramic coating led to a reduction in the corrosion rate. A slight increase in the corrosion rate was observed for samples with bioactive drug-containing coatings compared to samples with drug-free coatings. Higher viability of human fibroblastic cells cultured in the extracts of the tested samples was noted for samples with a bilayer coating compared to a ceramic coating. The addition of gentamicin in the bioactive coatings had no significant effect on the viability value. Antibacterial tests proved the antibacterial activity of samples with a gentamicin-loaded coating layer against Escherichia coli and Staphylococcus aureus strains. A detailed study of the release of gentamicin from the prepared coatings revealed a different mechanism of drug release from the ceramic and the ceramic/polymer coating. Furthermore, it was found that the drug was released more slowly and uniformly from the bilayer coating. It is therefore possible to adjust the amount and duration of drug release from the bioactive coating by the thickness of the upper polymer layer. Incorporation of an antibiotic in a combined ceramic/polymer coating enabled the creation of a high-performance bioactive coating for Fe bone implants with the possibility to release a drug in the vicinity of the implant in a controlled manner to address the needs of the patient.

Prevention of early thrombosis in transplanted vein model by encapsulation with tirofiban microneedle drug delivery system

Early thrombosis following coronary artery bypass grafting (CABG) surgery leads to perioperative myocardial infarction, which causes difficulties for clinicians and patients. Moreover, once perioperative myocardial infarction occurs, the mortality rate is extremely high. In recent years, microneedle (MN) drug delivery systems have become a research hotspot with broad clinical application prospects. These systems are capable of achieving sustained, safe, and painless local drug release. In cardiovascular applications, MNs maximize local anticoagulant effects, inhibit endometrial hyperplasia, and reduce systemic side effects. We speculate that a MN drug delivery system can be used to target transplanted veins to inhibit their thrombosis and reduce the incidence of perioperative myocardial infarction after CABG surgery. Therefore, this study developed a hyaluronic acid MN patch loaded with tirofiban and conducted preliminary physicochemical tests. The safety, efficacy, biocompatibility, and targeting of the MN system were evaluated usingin vitroandin vivoexperiments using a jugular vein transplantation model. The results indicate that the MN system has excellent physical properties, safety, effectiveness, biocompatibility, and strong targeting, which can effectively inhibit early local thrombus formation. In addition, the observation of early postoperative endometrial hyperplasia activation provides a foundation for future research.

Single-Component Starch-Based Hydrogels for Therapeutic Delivery.

Hydrogels are interesting materials as delivery systems of various therapeutic agents, mainly due to the water-swollen network and the localized and sustained drug release. Herein, single-component starch-based hydrogels with enhanced degradation rates were produced by applying a facile synthesis and proposed for a novel delivery system of therapeutic molecules. Starch was oxidized with sodium periodate in water and mild conditions to generate aldehyde derivatives that, after a freeze-thaw procedure, were allowed to compact and stable hydrogels. Oxidized starch was also cross-linked with asparagine through a Schiff base reaction to link the active molecule directly to the polysaccharide structure. The materials were structurally and morphologically characterized, and the ability to adsorb and release over time an active molecule was proven by qNMR spectroscopy. The cytotoxicity was evaluated on CAL-27 cell line (oral squamous cell carcinoma). Results indicated that synthesized hydrogels lead to a "frozen proliferative" state on cells due to the swelling capability in the cell medium. This behavior was confirmed by flow cytometry data indicating the hydrogels induced less "early apoptosis" and more "late apoptosis" in the cells, compared to the untreated control. Since the proposed materials are able to control the cell proliferation, they could open a new scenario within the field of precise therapeutic applications.

Trojan Horse Strategy for Wireless Electrical Stimulation-Induced Zn2+ Release to Regulate Neural Stem Cell Differentiation for Spinal Cord Injury Repair.

Due to the uncertain differentiation of neural stem cells (NSCs), replenishing lost neurons by endogenous neural differentiation to repair spinal cord injury (SCI) remains challenging. The electrical stimulation-induced drug release is a promising approach for the localized and controlled release of drugs to regulate the differentiation of NSCs into neurons. Here, we developed Zn-PDA@BT nanoparticles acted as Trojan Horse to enter cells through endocytosis for Zn2+-controlled release therapy by the potentials generated by the piezoelectric effect. Due to the presence of polydopamine (PDA), under ultrasound stimulation, the electrical signal derived from the piezoelectric effect of barium titanate nanoparticles can be attracted to the surface of Trojan Horse nanoparticles to facilitate the controlled release of Zn2+. And Zn2+ bonded with PDA can increase the intracellular Zn2+ concentration within mouse-derived NSCs (mNSCs) to regulate the differentiation of mNSCs, which could enhance excitatory neuronal differentiation and inhibit astrocyte differentiation of mNSCs by activating the TGF-β and p53 pathways. More importantly, this Trojan Horse therapy allowed mNSCs to differentiate into mature neurons in 5 days, while the natural differentiation process took 10 days. Moreover, the transplantation of mNSC-ingested Zn-PDA@BT nanoparticles effectively replenished lost neurons at the damaged site and promoted function recovery after SCI in vivo, demonstrating the great potential of electrical stimulation-induced Zn2+ release for SCI repair.

Electrospun nanofibers for localized drug release of a neuroprotective natural extract of Usnea ghattensis

This research is based on the incorporation of the methanolic extract of the Usnea ghattensis into poly (caprolactone) (PCL) nanofibers (NFs) to investigate the capacity in reducing reactive oxygen species (ROS). PCL-NFs were fabricated by the electrospinning technique and are investigated as potential dressing material focused on the release of usnic acid (PCL-USNIC NFs), and its encapsulation efficiency and kinetic release were analyzed by high performance liquid chromatography (HPLC). This investigation was performed by analyzing the usnic acid concentration as a function of the distance from the mat center point. The kinetic release analysis is also developed with the usnea ghattensis extract (PCL-USNEA NFs), performing a metabolomic analysis of the released molecules as a function of time by nuclear magnetic resonance (NMR). Usnic acid was revealed as the most relevant compound together with other molecules, such as sucrose, mannitol, arabitol or glycerol that generate a positive matrix effect on the release of usnic acid. Finally, we analize the cytotoxicity and the neuroprotective effect of PCL-USNEA and PCL-USNIC NFs using a human neuroblastoma cell line model. Negligible toxicity was appreciated for both polymeric systems, showing high protective effects in presence of highly oxidative environment (e.g. in presence of H2O2).

A pH-Responsive Ti-Based Local Drug Delivery System for Osteosarcoma Therapy.

Osteosarcoma is one of the major bone cancers, especially for youngsters. The current treatment usually requires systemic chemotherapy and the removal of bone tumors. Titanium (Ti)-based implants can be modified as local drug delivery (LDD) systems for controllable and localized chemotherapeutic drug release. In this work, a pH-responsive Ti-based LDD prototype was designed by introducing polydopamine (PDA) to release doxorubicin (DOX) around osteosarcoma cells with low pH. Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and a contact angle meter were applied for surface characterization. Both direct and indirect cell culture modes were performed for biocompatibility and biofunction assessments. The results indicate that the Ti-based LDD prototype exhibits significant pH-dependent DOX release. The cumulative release can reach up to approximately 40% at pH = 6.0 after 72 h, but only around 20% at pH = 7.4. The Ti-based LDD implant shows good biocompatibility with approximately 93% viability of MC3T3 cells after direct culture in vitro for 24 h. Both direct and indirect culture modes verify the good anti-osteosarcoma function of the LDD implant, which should be attributed to the pH-responsive release of DOX.

Icariin-loaded chitosan/β-glycerophosphate thermosensitive hydrogel enhanced infection control and bone regeneration in canine with infectious bone defects.

Faced with infectious bone defects, the development of a thermosensitive hydrogel containing icariin (ICA) represents a promising therapeutic strategy targeting infection control and bone regeneration. In this study, we prepared and evaluated the physicochemical properties, in vitro and in vivo drug release, antimicrobial activity, anti-inflammatory properties, and bone repair effects of ICA/Chitosan/β-Glycerophosphate (ICA/CTS/β-GP) thermosensitive hydrogel. Our findings demonstrate that the ICA/CTS/β-GP thermosensitive hydrogel undergoes a liquid-to-gel transition at body temperature, which is crucial for maintaining local drug release at the defect site. Additionally, the hydrogel exhibited sustained release of ICA over 28days, showing high antimicrobial activity against Staphylococcus aureus and good biocompatibility in blood compatibility tests. In a canine model of infectious bone defects, the ICA/CTS/β-GP thermosensitive hydrogel showed effective infection control and modulated inflammation, vascular formation, and bone factor expression, while also activating the Wnt/β-catenin signaling pathway. In conclusion, the ICA/CTS/β-GP thermosensitive hydrogel could control infection and repair bone tissue. Its antimicrobial and osteogenic properties provide hope for its clinical application.

Skin Cancer Treatment with Subcutaneous Delivery of Doxorubicin-Loaded Gelatin Nanoparticles and NIR Activation.

Subcutaneous (SC) administration of chemotherapeutics combined with near-infrared (NIR) light activation can effectively target skin tumors by triggering localized drug release and enhancing cytotoxic effects. In this study, we developed NIR-responsive indocyanine green (ICG) and the chemotherapeutic agent doxorubicin (Dox) loaded into gelatin nanoparticles (NPs) for SC delivery in a skin tumor-bearing mouse model. Histological examination (hematoxylin and eosin staining) confirmed the successful delivery and swelling behavior of the Dox/ICG-loaded gelatin NPs at the SC site. In vitro and in vivo experiments demonstrated that NIR activation of the Dox/ICG-loaded gelatin NPs generated significant photothermal heat (48 and 46 °C), leading to targeted drug release and a substantial reduction in skin tumor size (from 15 to 3 mm3). Our findings suggest that this dual-modality approach of SC chemotherapeutic administration and NIR-triggered photothermal therapy can concentrate cytotoxic drugs at the tumor site, offering a promising strategy for improving skin cancer treatment.

Intraoperative Cavity Local Delivery System with NETs-Specific Drug Release for Post-Breast Cancer Surgery Recurrence Correction.

Postoperative breast cancer recurrence is tricky due to the limited therapeutic options. Transforming growth factors-β (TGF-β) is vital in promoting postoperative tumor recurrence. However, conventional blocking strategies fail to satisfy both bio-safety and sufficient relapse correction. Neutrophil extracellular traps (NETs) are essential for the spatiotemporal dynamics of TGF-β at tumor-resection sites, whose unique mechanism for local TGF-β amplification could remarkably increase the risk of relapse after surgery. Herein, the principle of NETs formation is ingeniously utilized to construct a surgical residual cavity hydrogel that mimics NETs formation. The hydrogel is prepared based on the electrostatic interaction between histidine (His) and sodium alginate (Alg). Then, arginine deiminase 4 (PAD4) protein is released during NETs formation. Simultaneously, the electrical property of His in hydrogel changes automatically, which further lead to promising localized release of anti-TGF-β. The hydrogel system can realize specific and selective drug release at targeted NETs site over a prolonged period while exhibiting excellent biocompatibility. Superior breast cancer recurrence inhibition is achieved by suppressing TGF-β and related indicators, impeding epithelial-mesenchymal transition (EMT) progression, and rectifying the locally exacerbated immunosuppressive environment within NETs. The novel NETs local microenvironment drug release functional hydrogel will provide inspiration for postoperative recurrence correction strategies.

Injectable, reversibly thermoresponsive captopril-laden hydrogel for the local treatment of sensory loss in diabetic neuropathy

A major and irreversible complication of diabetes is diabetic peripheral neuropathy (DPN), which can lead to significant disability and decreased quality of life. Prior work demonstrates the peptide hormone Angiotensin II (Ang II) is released locally in neuropathy and drives inflammation and impaired endoneurial blood flow. Therefore, we proposed that by utilizing a local thermoresponsive hydrogel injection, we could deliver inhibitors of angiotensin-converting enzyme (ACE) to suppress Ang II production and reduce nerve dysfunction in DPN through local drug release. The ACE inhibitor captopril was encapsulated into a micelle, which was then embedded into a reversibly thermoresponsive pluronics-based hydrogel matrix. Drug-free and captopril-loaded hydrogels demonstrated excellent product stability and sterility. Rheology testing confirmed sol properties with low viscosity at ambient temperature and increased viscosity and gelation at 37 °C. Captopril-loaded hydrogels significantly inhibited Ang II production in comparison to drug-free hydrogels. DPN mice treated with captopril-loaded hydrogels displayed normalized mechanical sensitivity and reduced inflammation, without side-effects associated with systemic exposure. Our data demonstrate the feasibility of repurposing ACE inhibitors as locally delivered anti-inflammatories for the treatment of sensory deficits in DPN. To the best of our knowledge, this is the first example of a locally delivered ACE inhibitor for the treatment of DPN.

3D-printed HA15-loaded β-Tricalcium Phosphate/Poly (Lactic-co-glycolic acid) Bone Tissue Scaffold Promotes Bone Regeneration in Rabbit Radial Defects.

In this study, a β-tricalcium phosphate (β-TCP)/poly (lactic-co-glycolic acid) (PLGA) bone tissue scaffold was loaded with osteogenesis-promoting drug HA15 and constructed by three-dimensional (3D) printing technology. This drug delivery system with favorable biomechanical properties, bone conduction function, and local release of osteogenic drugs could provide the basis for the treatment of bone defects. The biomechanical properties of the scaffold were investigated by compressive testing, showing comparable biomechanical properties with cancellous bone tissue. Furthermore, the microstructure, pore morphology, and condition were studied. Moreover, the drug release concentration, the effect of anti-tuberculosis drugs in vitro and in rabbit radial defects, and the ability of the scaffold to repair the defects were studied. The results show that the scaffold loaded with HA15 can promote cell differentiation into osteoblasts in vitro, targeting HSPA5. The micro-computed tomography scans showed that after 12 weeks of scaffold implantation, the defect of the rabbit radius was repaired and the peripheral blood vessels were regenerated. Thus, HA15 can target HSPA5 to inhibit endoplasmic reticulum stress which finally leads to promotion of osteogenesis, bone regeneration, and angiogenesis in the rabbit bone defect model. Overall, the 3D-printed β-TCP/PLGA-loaded HA15 bone tissue scaffold can be used as a substitute material for the treatment of bone defects because of its unique biomechanical properties and bone conductivity.