Drug Delivery Research Articles

Efficacy and safety of transhepatic arterial chemoembolization with drug-loaded microspheres in unresectable primary liver cancer

BACKGROUND Transhepatic arterial chemoembolization (TACE), as a local treatment, has been widely used in the treatment of unresectable liver cancer. The introduction of drug carrier microspheres has brought new hope for the therapeutic effect of TACE. Microspheres can realize the slow release and directional delivery of drugs, reduce systemic toxicity and improve local curative effect. AIM To compare the effectiveness of traditional transcatheter arterial chemoembolization against microsphere-assisted transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma that is incurable. METHODS We searched the PubMed, Embase, Cochrane Library, and CNKI databases for clinical trials of drug-luting beads TACE (DEB-TACE) vs conventional TACE (cTACE) for the treatment of unresectable liver cancer. We screened references based on inclusion and exclusion criteria and then selected valid data for meta-analysis using RevMan 53 software. The complete response (CR) rate, partial response (PR) rate, postoperative stable disease (SD) rate, and 6-month and 12-month survival rates were compared. RESULTS A total of 12 articles were included, including 1177 patients, 519 of whom received DEB-TACE and 658 of whom received cTACE. The CR rate in the DEB-TACE group was much greater than that in the cTACE group [relative risk (RR) = 1.42, 95%CI: 1.18–1.72, P = 0.0002]. The 12-month survival rate significantly increased (RR = 1.09; 95%CI: 1.01- 1.17, P = 0.03); the PR rate (RR = 1.13; 95%CI: 0.97-1.30, P = 0.12); the SD rate (RR = 0.82; 95%CI: 0.64-1.05, P = 0.12); and the 6-month survival rate (RR = 1.05; 95%CI: 1.00-1.10, P = 0.07). There was no significant difference (P < 0.05). CONCLUSION Compared with those of iodized oil TACE, the drug-loaded microspheres tended to have therapeutic advantages.

Retraction Note: Alkali metal-doped borospherenes M@C4B32 (M = K, Na, and Li) as a highly efficient alternative for the drug delivery.

Retraction Note: Alkali metal-doped borospherenes M@C4B32 (M = K, Na, and Li) as a highly efficient alternative for the drug delivery.

GFP Farnesylation as a Suitable Strategy for Selectively Tagging Exosomes.

Exosomes are small extracellular vesicles (EVs) constituting fully biological, cell-derived nanovesicles with great potential in cell-to-cell communication and drug delivery applications. The current gold standard for EV labeling and tracking is represented by fluorescent lipophilic dyes which, however, importantly lack selectivity, due to their unconditional affinity for lipids. Herein, an alternative EV fluorescent labeling approach is in-depth evaluated, by taking advantage of green fluorescent protein (GFP) farnesylation (GFP-f), a post-translational modification to directly anchor GFP to the EV membrane. The performance of GFP-f is analyzed, in terms of selectivity and efficiency, in several typical EV experimental setups such as delivery in recipient cells, surface engineering, and cargo loading. First, the capability of GFP and GFP-f to label exosomes was compared, showing significantly higher GFP protein levels and fluorescence intensity in GFP-f- than in GFP-labeled exosomes, highlighting the advantage of directly anchoring the GFP to the EV cell membrane. Then, the GFP-f tag was further compared to Vybrant DiD lipophilic dye labeling in exosome uptake studies, by capturing EV intracellular fluorescence in a time- and concentration-dependent manner. The internalization assay revealed a particular ability of GFP-f to monitor the uptake of tagged exosomes into recipient cells, with a significant peak of intensity reached 12 h after administration by GFP-f but not Vybrant-labeled EVs. Finally, the GFP-f labeling capability was challenged in the presence of a surface modification of exosomes and after transfection for siRNA loading. Results showed that both procedures can influence GFP-f performance compared to naïve GFP-f exosomes, although fluorescence is importantly maintained in both cases. Overall, these data provide direct insight into the advantages and limitations of GFP-f as a tagging protein for selectively and accurately tracking the exosome route from isolation to uptake in recipient cells, also in the context of EV bioengineering applications.

Enhanced diffusion through multivalency.

The diffusion of macromolecules, nanoparticles, viruses, and bacteria is essential for targeting hosts or cellular destinations. While these entities can bind to receptors and ligands on host surfaces, the impact of multiple binding sites-referred to as multivalency-on diffusion along strands or surfaces is poorly understood. Through numerical simulations, we have discovered a significant acceleration in diffusion for particles with increasing valency, while maintaining the same overall affinity to the host surface. This acceleration arises from the redistribution of the binding affinity of the particle across multiple binding ligands. As a result, particles that are immobilized when monovalent can achieve near-unrestricted diffusion upon becoming multivalent. Additionally, we demonstrate that the diffusion of multivalent particles with a rigid ligand distribution can be modulated by patterned host receptors. These findings provide insights into the complex diffusion mechanisms of multivalent particles and biological entities, and offer new strategies for designing advanced nanoparticle systems with tailored diffusion properties, thereby enhancing their effectiveness in applications such as drug delivery and diagnostics.

Self-Assembled DNA-Collagen Bioactive Scaffolds Promote Cellular Uptake and Neuronal Differentiation.

Different modalities of DNA/collagen complexes have been utilized primarily for gene delivery studies. However, very few studies have investigated the potential of these complexes as bioactive scaffolds. Further, no studies have characterized the DNA/collagen complex formed from the interaction of the self-assembled DNA macrostructure and collagen. Toward this investigation, we report herein the fabrication of novel bioactive scaffolds formed from the interaction of sequence-specific, self-assembled DNA macrostructure and collagen type I. Varying molar ratios of DNA and collagen resulted in highly intertwined fibrous scaffolds with different fibrillar thicknesses. The formed scaffolds were biocompatible and presented as a soft matrix for cell growth and proliferation. Cells cultured on DNA/collagen scaffolds promoted the enhanced cellular uptake of transferrin, and the potential of DNA/collagen scaffolds to induce neuronal cell differentiation was further investigated. The DNA/collagen scaffolds promoted neuronal differentiation of precursor cells with extensive neurite growth in comparison to the control groups. These novel, self-assembled DNA/collagen scaffolds could serve as a platform for the development of various bioactive scaffolds with potential applications in neuroscience, drug delivery, tissue engineering, and in vitro cell culture.

Recent advances in synthesis and bio-applications of natural stabilizers for metal nanoparticles

Due to their exceptional physicochemical properties, the synthesis and application of metal nano-particles gained significant traction and a grip in industries and scientific fields or regions. However, the thermodynamic instability of metal nanoparticles poses or leads to challenges in their controlled synthesis and stabilization. To address this stability and the immobilization strategies, natural polymers such as cellulose, starch, alginate, chitosan, and hyaluronic acid have been explored for their non-toxic, biodegradable, and environmentally friendly characteristics. Recent advances in nanotechnology have led to an increased focus on these natural polymer’s utilization as effective stabilizers for diverse metal nanoparticles. This review comprehensively examines recent advances in utilizing these natural polymers as stabilizers for metal nanoparticles. Synthesis methods, stabilization mechanisms, and applications spanning catalysis, sensing, drug delivery, and biomedical imaging are discussed. Challenges such as scalability and reproducibility are addressed, alongside future directions for research and development. In this review, our goal is to encourage continued research and creativity in sustainable nanomaterials. By doing so, we hope to advance the development of adaptable and environmentally friendly nanoparticles that find applications across various industries.

ROS Responsive Cerium Oxide Biomimetic Nanoparticles Alleviates Calcium Oxalate Crystals Induced Kidney Injury via Suppressing Oxidative Stress and M1 Macrophage Polarization.

Emerging studies have demonstrated that M1 macrophage polarization and oxidative stress play important roles in calcium oxalate (CaOx) induced kidney injury, which leads to increased crystals deposition. ROS scavenging nanozymes and kidney-targeted nanoparticles for antioxidant drugs delivery have emerged as an arisen methodology for kidney injury therapy. However, cell membrane biomimetic-modified nanozymes as anti-inflammatory drug delivery systems for the treatment of kidney injury is rarely reported. Herein, the ROS responsive red blood cell-membrane-coated resatorvid-loaded cerium oxide nanoparticles (RBCM@CeO2/TAK-242) are constructed to suppress CaOx induced kidney injury and crystals deposition. In vitro, RBCM@CeO2/TAK-242 shows effective internalization by renal tubular epithelial cells, along with demonstrated antioxidative, anti-inflammatory, and macrophage reprogramming effects. Glyoxalate(Gly)-induced renal CaOx crystals mouse model is established, RBCM@CeO2/TAK-242 shows excellent injured kidney targeting and biosafety, and could effectively suppress CaOx induced kidney injury and crystals deposition. RBCM@CeO2/TAK-242 has a dual protective effect by both inhibiting oxidative stress and modulating macrophage polarization in vivo. In addition, RNA seq analysis reveals that RBCM@CeO2/TAK-242 protects against CaOx induced kidney injury via suppressing the TLR4/NF-κB pathway. This study provides an innovative strategy for RBCM@CeO2/TAK-242 as injured kidney targeting and dual protective effects for the treatment of CaOx induced kidney injury and crystals deposition.

Advanced MicroRNA delivery for lung inflammatory therapy: surfactant protein A controls cellular internalisation and degradation of extracellular vesicles

IntroductionAlveolar macrophages (AMs) are the first line of defence against pathogens that initiate an inflammatory response in the lungs and exhibit a strong affinity for surfactant protein A (SP-A). Extracellular...

A platform of gold nanoparticles coated with silica as controlled drug delivery for application in cancer treatment

A platform of gold nanoparticles coated with silica as controlled drug delivery for application in cancer treatment

Double-blinded, randomized tolerance study of a biologically enhanced Nanogel with endothelin-1 and bradykinin receptor antagonist peptides via intra-articular injection for osteoarthritis treatment in horses

BackgroundOsteoarthritis is a leading cause of pain and retirement in athletic horses. Hydro-expansive functionalized nanogels, acting as Drug Delivery Systems, constitute one of the current therapeutic prospects. These nanogels have the potential to combine mechanical benefits through polymers with the biological effect of prolonged release of bioactive molecules. The purpose of this double-blinded randomized tolerance study versus negative control was to evaluate the response of healthy joints to a single injection of the expected efficient dose (further referred to as the trial dose) and overdose of nanogels composed of chitosan and hyaluronic acid and featuring a type A endothelin receptor antagonist and a type B1 bradykinin receptor antagonist. The metacarpophalangeal joints of 8 healthy horses were randomly injected with 2.4 mL of functionalized nanogels and 2.4 mL of saline as control on the contralateral limb. Injections were repeated twice at one-week intervals, followed by injection of a triple dose of nanogel on week four. Clinical, ultrasonographic and synovial fluid cellular and biochemical follow-ups were performed up to three months following the first injection.ResultsNo change in general clinical parameters, lameness or sensitivity to passive flexion of the fetlocks was noted. Mild to moderate synovitis was noted on the day following injection in the treated group, with a significant difference (p < 0.05) compared to the control group. It spontaneously resolved on day 3 following the injections and did not increase with repeated injections. Similar effects were noted after injection of the triple dose but lasted for a week. Synovial fluid markers of inflammation also showed a transient significant increase in the treated group one week after each injection, but no differences were detected at the end of the study.ConclusionsInjections of the expected therapeutic dose of functionalized nanogel in healthy joints induced a mild transient inflammatory response in the joint. Three injections of the trial dose at one-week intervals and injection of thrice the trial dose induce a mildly greater inflammation without harmful effects on joints. Functionalized nanogels are well tolerated prospects for the treatment of osteoarthritis in horses. Their beneficial effects on arthritic joints have yet to be evaluated to determine their therapeutic potential.

Aerosol Fluorescent Labeling via Probe Molecule Volatilization.

The physicochemical properties of aerosols, including hygroscopicity, phase state, pH, and viscosity, influence important processes ranging from virus transmission and pulmonary drug delivery to atmospheric light scattering and chemical reactivity. Despite their importance, measurements of these key properties in aerosols remain experimentally challenging due to small particle sizes and low mass densities in air. Fluorescence probe spectroscopy is one of the only analytical techniques that is capable of experimentally determining these properties in situ in a nondestructive and minimally perturbative manner. However, the application of fluorescence probe spectroscopy to important classes of aerosols including exhaled respiratory and ambient atmospheric aerosols has been limited due to a typical reliance on premixing the probe molecule with particle constituents prior to particle generation, which is not always possible. Here, a method for aerosol fluorescent labeling based on probe molecule volatilization is developed. The method is first applied to label model polyethylene glycol (PEG) aerosols with two different polarity-sensitive probes, Nile red and Prodan. The similarity of the relative humidity-dependent fluorescent emission of each probe between prelabeled and volatilized-probe PEG particles validated the methodology. A preliminary application of the technique to indicate the hygroscopicity of artificial saliva respiratory particles and model atmospheric secondary organic aerosol particles is demonstrated. The methodology developed here paves the way for future studies applying powerful fluorescent probe-based analytical techniques to study exhaled or natural aerosols for which fluorescent prelabeling is not possible.

Synthesis of a PVA-GO drug delivery system for sustained release of 4-methyl umbelliferon

Introduction 4-methyl umbelliferon (4MU) is a coumarin with anti-inflammatory, anti-thrombotic, enzyme-inhibiting, and antioxidant properties. Despite the benefits of the compound, it is eliminated very quickly from the blood circulation through the liver, kidney, and digestive system due to its hydrophobic properties. In this study we proposed to improve the durability of 4MU by binding of 4MU to poly vinyl alcohol (PVA) and graphene oxide (GO). Methods The PVA-4MU-GO complex was synthesized and characterized. Release of 4MU from the complex was investigated. H9C2 cells viability was investigated and the entry of complex to the cell was analyzed using flow cytometry. Result UV-Vis and FTIR studies confirmed the interaction of 4MU with PVA and GO. SEM measurement also revealed a particle size around 101 nm for PVA-4MU-GO complexes. The obtained results confirmed the assembly of PVA-4MU-GO. A continuous drug release for 8 d (160 h) was achieved. Cytotoxic studies on H9C2 cell showed that PVA-4MU-GO complex is dependent to the concentration of GO and also the relation of 4MU to GO. Sustained release and penetration of PVA-4MU-GO complex into the H9C2 cell were observed. Conclusion PVA-4MU-GO complex is recommended as an alternative for 4MU. Synthesis the complex of PVA-4MU-GO, verifying the correct binding, showing the in vitro release of the 4MU, as well as checking its toxicity and its gradual entry into the H9C2 cell, were performed in this study.

Delivery of Encapsulated Intelligent Engineered Probiotic for Inflammatory Bowel Disease Therapy.

Engineered bacterial therapy holds enormous potential for treating intestinal diseases, employing synthetic biology techniques to achieve localized drug delivery within intestines. However, effective delivery of engineered bacteria to lesion sites and ensuring sustained colonization remain challenging. Here, a mucus encapsulated microsphere gel (MM) delivery system is developed to encapsulate genetically engineered bacteria capable of detecting and treating enteritis. The MM delivery system features an external mucosal coating composed of hyaluronic acid and epigallocatechin gallate, along with internal microspheres of highly biocompatible polyserine modified alginates encapsulating with the engineered probiotics. The MM delivery system effectively protects engineered bacteria harsh environment in stomach and significantly improves intestinal adhesion of the probiotics, extending colonization up to 24h, and does not affect the entry of biomarker or release of Avcystatin. It exhibits notable diagnostic and therapeutic efficacy in inflammatory bowel disease models, thus facilitating the advancement of live biotherapeutic products toward clinical application.

Co-culture system of breast cancer and normal cells to investigate inflammation: using doxorubicin encapsulated in adipose-derived exosomes.

Doxorubicin (DOX) chemotherapy for breast cancer is an effective treatment option, but it also has disadvantages. Exosomes (EXOs) have safely and successfully transported DOX and reduced its adverse effects; however, its use is still being explored. In this study, a co-culture system of malignant and non-malignant breast cells was used to generate an in vitro model reflecting the in vivo cellular microenvironment, and the effects of this treatment were investigated by examining inflammatory genes. Extracellular matrices (EXOs) were extracted from mesenchymal stem cells derived from human adipose tissue by ultracentrifugation. Later, Western blotting, dynamic light scattering (DLS) and transmission electron microscopy methods were used to examine the properties of the EXO. DOX was encapsulated in the EXOs by sonication and the loading rate was measured by spectrophotometry. In the current study, a co-culture system was used to investigate the cytotoxic effects of free DOX and DOX encapsulated in EXOs (EXO-DOX) on various breast cell lines, including MCF-7, MCF-10A, MDA-MB-231, and A-MSC. Additionally, the expression levels of inflammatory cytokines (IL-1β, IL-6, IL-10, and TNF-α) were examined. Methylthiazolyldiphenyl-tetrazolium bromide assay demonstrated that free DOX showed the highest cytotoxicity against MCF-10A cells, followed by MCF-7 cells. Conversely, EXO-DOX indicated a greater effect on MCF-7 cells and had a lower IC50 compared to MDA-MB-231 cells. Free DOX significantly downregulated the expression of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), particularly in MCF-7 and MCF-10A cells, while concurrently upregulating IL-10 expression. EXO-DOX induced a more significant alteration in cytokine expression than the control and free DOX treatment groups. The co-culture system revealed a synergistic effect of free DOX on cancer cells while simultaneously mitigating the toxic effects of DOX on normal cells. This study suggests that EXO-DOX has promising potential as a targeted drug delivery system that could potentially improve therapeutic efficacy and minimize off-target toxicity.

Optimizing Ligand Valency to Maximize Tendon Accumulation of Peptide-Targeted Nanoparticles.

In many tissues, including musculoskeletal tissues such as tendon, systemic delivery typically results in poor targeting of free drugs. Hence, we previously developed a targeted drug delivery nanoparticle (NP) system for tendon healing, leveraging a tartrate resistant acid phosphatase (TRAP) binding peptide (TBP) ligand. The greatest tendon targeting was observed with NPs functionalized with 30 000 TBP ligands per NP at day 7 during the proliferative healing phase, relative to the inflammatory (day 3) and early remodeling (day 14) phases of healing. Nevertheless, TRAP activity varies throughout healing and, therefore, may offer an opportunity for optimizing temporal therapeutic targeting through multivalent interactions. Hence, in this study, we hypothesized that the ligand density (9000-55,000 TBPs per NP) can optimize tendon accumulation on the basis of variable TRAP levels. The multivalent nanoparticles were loaded with three different fluorophores. In vitro, the ligand density and fluorophore had no effect on the physicochemical properties of the NPs, including size, charge, polydispersity index, or dye loading efficiency; however, the TRAP binding affinity correlated positively with the ligand density. In vivo, the ligand density correlated positively with NP homing and retention in the tendon, establishing opportunities to leverage ligand density for tendon targeting across the tendon healing cascade, during aging, and in other tendon pathologies, including tendinopathies.

Toward Intracellular Delivery: Aliphatic Polycarbonates with Pendant Thiol-Reactive Thiosulfonates for Reversible Postpolymerization Modification.

Postpolymerization modifications are valuable techniques for creating functional polymers that are challenging to synthesize directly. This study presents aliphatic polycarbonates with pendant thiol-reactive groups for disulfide formation with mercaptans. The reductive responsive nature of this reaction allows for reversible postpolymerization modifications on biodegradable scaffolds. Six-membered cyclic carbonate monomers with pendant thiosulfonate groups were synthesized and polymerized using controlled organocatalytic ring-opening polymerization, yielding polymers with narrow molecular weight dispersities (Đ = 1.2) and intact reactive thiosulfonate side chains. Reversible modification with benzyl mercaptans achieved high degrees of disulfide modification. Additionally, thiol-reactive carbonate monomers were block-copolymerized onto polyethylene glycol (mPEG113) and then converted into benzyl disulfides, while the block copolymers' hydroxyl end groups remained available for fluorescent dye labeling. The amphiphilic block copolymers self-assembled in water into micelles (∼33 nm diameter), capable of encapsulating hydrophobic molecules. These micelles successfully delivered hydrophobic dyes into macrophages, indicating the potential for intracellular drug delivery.

Trends in Photopolymerization 3D Printing for Advanced Drug Delivery Applications.

Since its invention in the 1980s, photopolymerization-based 3D printing has attracted significant attention for its capability to fabricate complex microstructures with high precision, by leveraging light patterning to initiate polymerization and cross-linking in liquid resin materials. Such precision makes it particularly suitable for biomedical applications, in particular, advanced and customized drug delivery systems. This review summarizes the latest advancements in photopolymerization 3D printing technology and the development of biocompatible and/or biodegradable materials that have been used or shown potential in the field of drug delivery. The drug loading methods and release characteristics of the 3D printing drug delivery systems are summarized. Importantly, recent trends in the drug delivery applications based on photopolymerization 3D printing, including oral formulations, microneedles, implantable devices, microrobots and recently emerging systems, are analyzed. In the end, the challenges and opportunities in photopolymerization 3D printing for customized drug delivery are discussed.

Application of Ordered Porous Silica Materials in Drug Delivery: A Review

Nanotechnology has significantly advanced various fields, including therapeutic delivery, through the use of nanomaterials as drug carriers. The biocompatibility of ordered porous silica materials makes them promising candidates for drug delivery systems, particularly in the treatment of cancer and other diseases. This review summarizes the use of microporous zeolites and mesoporous silica materials in drug delivery, focusing on their physicochemical properties and applications as drug carriers. Special emphasis is placed on strategies for encapsulation and functionalization, highlighting their role in enhancing drug loading and enabling targeted delivery. In conclusion, while ordered porous silica materials hold great potential for drug delivery systems, certain challenges remain.

Quantifying interstitial fluid by direct osmotic pressure measurements in vivo via telemetry-enabled Nanofluidic implants

Interstitial fluid (IF) is pivotal in maintaining balance within tissues and organs, facilitating molecular transport and supporting homeostasis. Various drug delivery systems, such as long-acting depots or implants, rely on IF to distribute drugs locally before they enter the bloodstream. The volume and accessibility of this fluid directly influence how drugs diffuse and the build-up of the osmotic pressure in areas with high drug concentration, ultimately impacting the performance of the delivery systems. Consequently, differences in free fluid availability contribute to discrepancies in drug delivery in vitro versus in vivo. Accurately estimating the volume of IF in vivo would significantly improve the design of in vitro drug release experiments and enhance the outcomes of animal studies. However, accurately measuring free IF and its effect on drug delivery systems in living organisms poses challenges. In response, we developed a reservoir-membrane subcutaneous (SQ) implant similar to a long-acting drug delivery system. The implant measures fluid availability in surrounding tissues by measuring real-time osmotic pressure changes resulting from fluid permeating through a nanoporous membrane, using an integrated pressure transducer and Bluetooth connectivity. By correlating in vitro and in vivo data using a computational model of molecular transport across the membrane, we estimated a 93 % reduction in free fluid availability in the subcutaneous tissue surrounding the implant as compared to our ideal in vitro setting with implant immersed within sink fluids. Applicable to various implantation sites, our study highlights a practical approach to directly assessing free fluid availability in different tissues, enhancing in vitro drug delivery experimental design and evaluating the performance of drug delivery systems in physiological contexts.

Heat-guided drug delivery via thermally induced crosslinking of polymeric micelles

Targeted drug delivery in response to external stimuli is therapeutically desirable, but long-term drug retention at the target site after stimulation is turned off remains a challenge. Herein, we present a targeted-delivery strategy via irreversible aggregation of drug carriers in response to mild external heating. We constructed two types of polymeric micelles, DBCO-TRM and Az-TRM, having a thermo-responsive polymer shell based on N-isopropylacrylamide (NIPAAm) and incorporating alkyne and azide moieties, respectively. Upon heating at 42 °C, the micelles aggregated through hydrophobic interaction between their dehydrated shells. Further, the azide moieties of Az-TRM become exposed on the surface due to the thermally shrinkage of the shells, thereby enabling crosslinking between the two types of micelles via azide-alkyne click chemistry to form irreversible aggregates. These aggregates were efficiently accumulated at tumor sites in mice by local heating after intravenous administration of a mixture of the micelles, and were well retained after cessation of heating due to their increased size. As proof of concept, we show that delivery of doxorubicin in this heat-guided drug delivery system dramatically improved the anti-tumor effect in a mouse model after a single treatment. Our results suggest that this platform could be an efficient tool for on-demand drug delivery.