Drug Delivery Systems Research Articles

Advances in Drug Delivery Systems for Lipophilic Drug Paclitaxel: Developments, Challenges, and Opportunities (A Review)

Advances in Drug Delivery Systems for Lipophilic Drug Paclitaxel: Developments, Challenges, and Opportunities (A Review)

Visualization of the degradation of long-acting microneedles and correlation of drug release in vivo based on FRET mechanism

This study introduces a live imaging technique for real-time, non-invasive monitoring of drug release from long-acting microneedles using FRET (Fluorescence Resonance Energy Transfer). Employing Cy5.5 and Cy7 as FRET pairs and levonorgestrel as the model drug, we fabricated microneedles with varying PLGA molecular weights, demonstrating distinct release profiles. The FRET-PLGA-10-MN demonstrated a rapid drug release profile, reaching nearly complete release within a two-day period, while FRET-PLGA-30-MN showed a sustained release over four days. Sensitized Emission FRET (SE-FRET) optimized the imaging process, providing a robust correlation between FRET signals and drug absorption. This method surpasses traditional pharmacokinetic studies by offering a more efficient and comprehensive analysis of microneedle release dynamics in vivo, paving the way for enhanced long-acting microneedle design and therapeutic outcomes. Statement of significance1. FRET technology was applied to microneedle drug delivery system for the first time, which realized real-time, quantitative and non-invasive monitoring of drug release process.2. The long-term microneedle technique was combined with sensitized emission method, and the FRET remaining ratio was innovatively used to investigate the FRET characteristics of microneedles, and the fluorescence ratio of FRET and donor double-channel was quantitatively calculated.3. The correlation between visual fluorescence images of FRET effect and semi-quantitative calculation results based on fluorescence intensity and drug release in vivo with drug-loaded microneedles was analyzed.

An alternative filament fabrication method as the basis for 3D-printing personalized implants from elastic ethylene vinyl acetate copolymer

In this work, a novel tool for small-scale filament production is presented. Unlike traditional methods such as hot melt extrusion (HME), the device (i) allows filament manufacturing from small material amounts as low as three grams, (ii) ensures high diameter stability almost independent of the viscoelastic behavior of the polymer melt, and (iii) enables processing of materials with rheological profiles specifically tailored toward fused filament fabrication (FFF). Hence, novel materials, previously difficult to process due to HME limitations, become easily accessible for FFF for the first time. Here, we showcase the production of highly flexible drug-free, and drug-loaded filaments based on ethylene-vinyl acetate polymers with a vinyl acetate content of 28 w% (EVA28) and unprecedented high melt flow rates of up to 400 g/10 min. Owing to their low viscosity, FFF with low print nozzle sizes of 250 μm was achieved for the first time for EVA28. These small nozzle diameters facilitate 3D-printing of high-resolution structures in small-dimensional dosage forms such as subcutaneous implantable drug delivery systems, which can later be used for personalization. Consequently, the material portfolio for FFF is tremendously broadened, allowing material and formulation optimization toward FFF, independent of a preliminary extrusion process.

A computational method for the component screening of carrier-free nanodrugs: exemplified by berberine

The emergence of carrier-free nanodrugs as a promising drug delivery system is a significant development in the field of pharmaceutical research. The research on molecules that can form carrier-free nanodrugs can facilitate the expansion of their applications. The capacity of molecules to self-assemble with other molecules is the foundation upon which their formation of carrier-free nanodrugs is based. In this paper, we present a computational method for evaluating the assembly ability of molecules in aqueous environments. The method begins with screening the optimal conformation of a single molecule in water, then simulates the assembly behavior of two molecules in water, and finally calculates the optimal conformation of dimer in water. In comparison to the original computational method, this method describes the effect of water on molecular assembly behavior with the greatest possible realism by utilizing high-precision water environments in each step. The accuracy of the method has been validated by classical experiments, while its rationality has been demonstrated by electronic structure calculations of single molecules and assemblies. Furthermore, we employ the method to investigate the assembly capabilities of 54 molecules in the presence of berberine. The results demonstrate that anthraquinone and flavonoid molecules readily form robustly bound assemblies with berberine. This method offers a relatively efficient approach to compositional screening of carrier-free nanodrugs, thereby contributing to the advancement of the field.

Advances in Drug Delivery Systems for the Treatment of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a common and catastrophic hematological neoplasm with high mortality rates. Conventional therapies, including chemotherapy, hematopoietic stem cell transplantation (HSCT), immune therapy, and targeted agents, have unsatisfactory outcomes for AML patients due to drug toxicity, off-target effects, drug resistance, drug side effects, and AML relapse and refractoriness. These intrinsic limitations of current treatments have promoted the development and application of nanomedicine for more effective and safer leukemia therapy. In this review, the classification of nanoparticles applied in AML therapy, including liposomes, polymersomes, micelles, dendrimers, and inorganic nanoparticles, is reviewed. In addition, various strategies for enhancing therapeutic targetability in nanomedicine, including the use of conjugating ligands, biomimetic-nanotechnology, and bone marrow targeting, which indicates the potential to reverse drug resistance, are discussed. The application of nanomedicine for assisting immunotherapy is also involved. Finally, the advantages and possible challenges of nanomedicine for the transition from the preclinical phase to the clinical phase are discussed.

Recent Developments in Using Microneedle Patch Technology as a More Efficient Drug Delivery System for Treating Skin Photoaging

Recent Developments in Using Microneedle Patch Technology as a More Efficient Drug Delivery System for Treating Skin Photoaging

Ultrafast continuous flow-dialysis for nanoparticle-based drug delivery systems via microfluidic-multiple buffer injector

Nanoparticle-based drug delivery systems (NP-DDS) have emerged as promising carriers for bioactive organic molecules due to their potential in enhancing therapeutic effects. However, traditional purification methods like batch dialysis and diafiltration can alter NP-DDS bio-physicochemical properties due to the lengthy process, prolonged coexistence with organic solvents, and external forces. To address this challenge, we developed an ultrafast flow-dialysis microfluidic module with dual channels separated by a membrane layer. The module leverages multiple buffer injectors (MBIs) to accelerate dialysis by injecting fresh buffer into multiple dialysis zones of bottom channel, refreshing the concentration gradients over the mixture sample in the upper channel to maximize mass transfer efficiency. Using this method for a dual drug-loaded liposome sample containing doxorubicin and curcumin, impurities (such as ethanol and un-trapped drugs) removal and buffer exchange were rapidly terminated within 15 min, continuously operating for ∼ 6 hrs with sequential membrane regeneration process. Importantly, unlike traditional methods, the MBI process maintains the initial uniformity in the size and distribution of liposomes with no leakage of the encapsulated drugs. In vitro HeLa cell tests reveal that the liposomes purified by MBI exhibited significantly higher cellular uptake (1.13 ∼ 1.67 fold), presumably due to the small and uniform size of liposomes, leading to improved anti-tumor effects. Notably, the MBI platform’s versatility was further verified by purifying a mixture of laccase enzyme and by removing the used organic solvents from various carriers (e.g., lipid-based, polymeric, and protein nanoparticles). It is envisioned that the outstanding performance of ultrafast dialysis will enables a continuous-flow downstream process for diverse nano-carriers by intensifying with extra steps in the manufacturing of nanomedicnes, including targeted drug delivery and cancer therapy.

Inhibition of bone resorption by nanoparticle drug delivery system

Inhibition of bone resorption by nanoparticle drug delivery system

Nasal administration of polysaccharides-based nanocarrier combining hemoglobin and diferuloylmethane for managing diabetic kidney disease

The management of diabetic kidney disease (DKD) faces challenges stemming from intricate pathologies and suboptimal biodistributions during drug delivery. Although clinically available anti-inflammatory agents hold considerable promise for treating DKD, their therapeutic effectiveness is limited when utilized in isolation. To address this limitation, we introduced a novel self-oriented nanocarrier termed F-GCS@Hb-DIF, designed to synergistically integrate the therapeutic diferuloylmethane (DIF), the polysaccharide fucoidan/glycol chitosan (F-GCS), and phototherapeutic hemoglobin (Hb). F-GCS@Hb-DIF demonstrated the capability to autonomously navigate toward diseased renal sites and directly release drugs into the cytoplasm of target cells following intranasal administration. This self-directed drug delivery system increased the accumulation of Hb and DIF at the target site by around 2–3 times compared to free drugs alone as per biodistribution data. This enhancement allowed F-GCS@Hb-DIF to adopt a synergistic approach in treating the complex pathologies of DKD during the two-week treatment period. This approach entails modulating immunity, promoting renal functional recovery with a tissue-protective effect, and alleviating renal inflammation. These results underscore the promising therapeutic potential of F-GCS@Hb-DIF in managing DKD and other degenerative diseases associated with diabetes.

Thermosensitive multivesicular liposomal hydrogel: a potential platform for loco-regional drug delivery in the treatment of osteomyelitis caused by antibiotic-resistant biofilm-forming bacteria.

Biofilm-mediated osteomyelitis presents significant therapeutic challenges. Given the limitations of existing osteomyelitis treatment approaches, there is a distinct need to develop a localized drug delivery system that is biocompatible, biodegradable, and capable of controlled antibiotic release. Multivesicular liposomes (MVLs), characterized by their non-concentric vesicular structure, distinct composition, and enhanced stability, serve as the system for a robust sustained-release drug delivery platform. In this study, various hydrogel formulations composed of poloxamer 407 and other hydrogels, incorporating vancomycin hydrochloride (VAN HL)-loaded MVLs (VAN HL-MVLs), were prepared and evaluated. The optimized VAN HL-MVL sol-gel system, consisting of poloxamer 407 and hyaluronic acid, successfully maintained drug release for up to 3 weeks and exhibited shear-thinning behavior at 37°C. While complete drug release from MVLs alone took place in 312 h, the hydrogel formulation extended this release to 504 h. The released drug effectively inhibited the Staphylococcus aureus biofilms growth within 24 h and methicillin-resistant S. aureus biofilms within 72 h. It also eradicated preformed biofilms of S. aureus and methicillin-resistant S. aureus in 96 and 120 h, respectively. This injectable in situ gel system incorporating VAN HL-MVLs holds potential as an alternative to undergoing multiple surgeries for osteomyelitis treatment and warrants further studies.

Emerging strategies for treating medical device and wound-associated biofilm infections.

Bacterial infections represent a significant global threat to human health, leading to considerable economic losses through increased healthcare costs and reduced productivity. One major challenge in treating these infections is the presence of biofilms - structured bacterial communities that form protective barriers, making traditional treatments less effective. Additionally, the rise of antibiotic-resistant bacteria has exacerbated treatment difficulties. To address these challenges, researchers are developing and exploring innovative approaches to combat biofilm-related infections. This mini-review highlights recent advancements in the following key areas: surface anti-adhesion technologies, electricity, photo/acoustic-active materials, endogenous mimicking agents, and innovative drug delivery systems. These strategies aim to prevent biofilm formation, disrupt existing biofilms, and enhance the efficacy of antimicrobial treatments. Currently, these approaches show great potential for applications in medical fields such as medical device and wound - associated biofilm infections. By summarizing these developments, this mini-review provides a comprehensive resource for researchers seeking to advance the management and treatment of biofilm-associated infections.

A nanozyme-based drug delivery system to amplify ferroptosis via MET inhibition and photodynamic therapy

A nanozyme-based drug delivery system to amplify ferroptosis via MET inhibition and photodynamic therapy

Enzyme-responsive microgel with controlled drug release, lubrication and adhesion capability for osteoarthritis attenuation

The treatment of osteoarthritis (OA) remains challenging due to the narrow therapeutic window and rapid clearance of therapeutic agents, even with intra-articular administration, resulting in a low treatment index. Recent advancements in local drug delivery systems have yet to overcome the issues of uncontrolled burst release and short retention time, leading to suboptimal OA treatment outcome. Herein, we developed a methacrylate-crosslinking hyaluronic acid (HA) microgel (abbreviated as CXB-HA-CBP) that covalently conjugates the anti-inflammatory drug celecoxib (CXB) via a metalloproteinase-2 (MMP-2)-responsive peptide linker (GGPLGLAGGC) and a collagen II binding peptide (WYRGRLC). The GGPLGLAGGC linker is specifically cleaved by the overexpressed MMP-2 enzyme within the OA joint, enabling the sustained and on-demand release of CXB entity. The synergistic action of CXB and HA effectively inhibited macrophage activation and reduced the production of pro-inflammatory cytokines, protecting chondrocytes from damage. Furthermore, the collagen II peptide introduced on the microgel surface enabled a cartilage-binding function to form an artificial lubrication microgel layer on the cartilage surface to reduce cartilage wear. The CXB-HA-CBP microgel showed an extended retention time of up to 18 days in the affected joint, leading to an effective OA treatment in rats. This sophistically designed microgel, characterized by the prolonged retention time, sustained drug delivery, and enhanced lubrication, presents a promising biomedicine for OA treatment. Statement of SignificanceA new methacrylate-crosslinking hyaluronic acid (HA) microgel, covalently conjugated with the celecoxib (CXB)-GGPLGLAGGC and the collagen II binding peptide (CBP, peptide sequence: WYRGRLC), was developed. The overexpressed MMP-2 in OA joint cleaved the GGPLGLAGGC linker to trigger the CXB moiety release. Besides, the CBP on the surface of microgels enabled a cartilage-attaching ability, resulting in a prolonged retention time and an improved lubrication property in joint. This advanced drug-loading microgel remarkably reduced macrophage activation and pro-inflammation cytokine production, while protecting the chondrocytes via a dual action of CXB and HA. This study demonstrated that the enzyme-responsive drug-loading microgel could serve as an platform to efficiently attenuate osteoarthritis.

Drug release profile of phenytoin-loaded starch-based biomaterials incorporating hierarchical microparticles with photothermal effects

This study aimed to synthesize phenytoin (PHT)-loaded water chestnut starch-based biomaterials and evaluate their drug release kinetics for use in transdermal drug delivery systems for antiepileptic therapy. Hierarchical microparticles (HMPs) extracted from human hair were also used to improve the PHT release efficiency. The physicochemical characteristics of PHT, HMPs, and the prepared biomaterials were evaluated by physical properties, antimicrobial activities, FE-SEM, FT-IR, XRD, 1H NMR, and 13C CPMAS solid-state NMR. The photothermal effect and the PHT release profile were confirmed through 808 nm NIR laser irradiation. After 30 min of the laser exposure, the temperature of the HMP-added biomaterials increased by 1.50–1.59 times compared to that of without the HMPs. PHT release in buffers and artificial skin test under NIR laser irradiation enhanced by 1.20–1.85 times owing to the photothermal effect. The release kinetics in pH buffer and artificial skin were determined using the Fickian diffusion and Korsmeyer-Peppas models. Additionally, to verify the transdermal penetration of PHT, drug-release simulations were conducted using rhodamine B in agar blocks and pig ears. The results implied that the photothermal effect of the HMPs enhanced the penetration of the drug.

Advancements of metallic nanoparticles: A promising frontier in cancer treatment.

The incidence of cancer is increasing and evolving as a major source of mortality. Nanotechnology has garnered considerable scientific interest in recent decades and can offer a promising solution to the challenges encountered with traditional chemotherapy. Nanoparticle utilization holds promise in combating cancer and other diseases, offering exciting prospects for drug delivery systems and medicinal applications. Metallic nanoparticles exhibit remarkable physical and chemical properties, such as their minute size, chemical composition, structure, and extensive surface area, rendering them versatile and cost-effective. Research has demonstrated their significant and beneficial impact on cancer treatment, characterized by enhanced targeting abilities, gene activity suppression, and improved drug delivery efficiency. By incorporating targeting ligands, functionalized metal nanoparticles ensure precise energy deposition within tumors, thereby augmenting treatment accuracy. Moreover, beyond their therapeutic efficacy, metal nanoparticles serve as valuable tools for cancer cell visualization, contributing to diagnostic techniques. Utilizing metal nanoparticles in therapeutic systems allows for simultaneous cancer diagnosis and treatment, while also facilitating controlled drug release, thus revolutionizing cancer care. This narrative review investigates the advancements of metal nanoparticles in cancer treatment, types and mechanisms in targeting cancer cells, application in clinical scenarios, and potential toxicity in medicine.

Picoplatin (II)-loaded chitosan nanocomposites as effective drug delivery systems: Preparation, mechanistic investigation of BSA/5-GMP/GSH binding and biological evaluations

The goal of the current study is to improve the characteristics and bioavailability of the drug picoplatin (PPt) by encapsulating it in chitosan nanoparticles (CS NPs) which allows for the targeted delivery of cytotoxic cargo to cancerous tissue, reducing toxic side effects and raising the therapeutic index. When picoplatin was delivered into the CS, it was able to produce an complex with CS (PPt@CS NPs) that had an appropriate particle size of 275 ± 10 nm, a reasonably low PDI of 0.15 ± 0.05, and high stability (ζ = −22.1 ± 0.3 mV). Since almost all pharmaceuticals work by binding to specific proteins or DNA, the in vitro binding mechanism and affinity of bovine serum albumin (BSA), low molecular building units of nucleic acids (5−GMP), and Glutathione (GSH) (considering that cisplatin resistance could be due to a reaction between cisplatin and GSH) to PPt and PPt@CS NPs were examined using stopped-flow and other spectroscopic approaches. Through two reversible processes, a rapid second-order binding followed by a slower first-order isomerization reaction, and a static quenching mechanism, PPt and PPt@CS NPs bind to BSA with relative reactivity of around (PPt)/(PPt@CS NPs) = 1/2.5. The 5−GMP interaction studies demonstrated that, in addition to changing the binding mechanism, PPt's encapsulation in CS increases its rate of reaction through coordination affinity. PPt interacted with 5-GMP via two reversible processes, a rapid second-order binding to phosphate followed by a slower first−order migration to the N7 of pyrimidine moiety. PPt@CS NPs showed weaker binding to GSH compared to PPt and hence PPt@CS NPs exhibits a lower resistance factor. It was also found that the in vitro drug release of PPt@CS NPs in PBS at pH 7.4 was steady, releasing 30% of the PPt in just 5 hours. Nonetheless, 75% of the release in a pH 5.4 solution containing 10 mM GSH—a solution that mimics the tumor microenvironment—shows that the PPt@CS NPs system is sensitive to GSH and specifically targets malignant tissue. The encapsulation of PPt in CS complex maintained its anticancer activity, as shown by an in vitro cell-survival assay on HepG2 cancer cell lines and also cleavage efficiency toward the minor groove of pBR322 DNA via the hydrolytic way. These findings collectively suggested that inclusion PPt in CS would be an effective strategy to formulate a novel picoplatin formulation intended for use as targeted anticancer treatment.

Synergistic antimicrobial effect of daptomycin and ethyl lauroyl arginate containing self-emulsifying drug delivery system against bacterial infections

This study aimed to enhance the antimicrobial properties of daptomycin by ion-pairing with ethyl lauroyl arginate (ELA) and incorporation in a self-emulsifying drug delivery system (SEDDS).Daptomycin was ion-paired with the ELA and the hydrophobic ion pair (HIP) was loaded into SEDDS. SEDDS 1 consisted of 15% oleic acid, 5% soy phosphatidylcholine, 10% cetyltrimethylammonium bromide (CTAB) in medium-chain triglycerides (MCT) at a concentration of 250 mg/ml, 20% benzyl alcohol, and 50% PG-4 caprate. SEDDS 2 comprised 10% soy phosphatidylcholine in MCT at a concentration of 53 mg/ml, 10% CTAB, 20% benzyl alcohol, and 60% PG-4 caprate. SEDDS were characterized regarding droplet size, polydispersity index (PDI), zeta potential, and stability. Cytotoxicity was evaluated on Caco-2, HeLa, and SW620 cells. Antimicrobial activity was assessed by agar diffusion studies and time-kill assays with Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Candida albicans.Both formulations showed a droplet size below 200 nm with a PDI < 0.4, a positive zeta potential, and robust thermodynamic stability. They exhibited low toxicity profiles while maintaining full antimicrobial efficacy on all tested pathogens. Compared to unformulated daptomycin, SEDDS 1 and 2 lowered the minimum inhibitory concentration (MIC) 5- and 8- fold for S. aureus and 10- and 30- fold for S. epidermidis, respectively. Bacterial killing time was 105 -fold shortened with SEDDS 1 and 106 -fold with SEDDS 2. Furthermore, HIP and SEDDS enhanced antibacterial activity against Candida albicans and Pseudomonas aeruginosa. According to these results, ion pairing of daptomycin with ELA and incorporation into SEDDS is a promising approach to improve the antimicrobial activity of this drug.

The Cervical and Meningeal Lymphatic Network as a Pathway for Retrograde Nanoparticle Transport to the Brain.

The meningeal lymphatic vessels have been described as a pathway that transports cerebrospinal fluid and interstitial fluid in a unidirectional manner towards the deep cervical lymph nodes. However, these vessels exhibit anatomical and molecular characteristics typical of initial lymphatic vessels, with the absence of surrounding smooth muscle and few or absent valves. Given its structure, this network could theoretically allow for bidirectional motion. Nevertheless, it has not been assessed as a potential route for nanoparticles to travel from peripheral tissues to the brain. We employed superparamagnetic iron oxide nanoparticles (SPIONs), exosomes loaded with SPIONs, gold nanorods, and Chinese ink nanoparticles. SPIONs were prepared via chemical coprecipitation, while exosomes were isolated from the B16F10 melanoma cell line through the Exo-Spin column protocol and loaded with SPIONs through electroporation. Gold nanorods were functionalized with polyethylene glycol. We utilized C57BL/6 mice for post-mortem and in vivo procedures. To evaluate the retrograde directional flow, we injected each nanoparticle solution in the deep cervical lymph node. The head and neck were fixed for magnetic resonance imaging and histological analysis. Here we show that extracellular vesicles derived from the B16F10 melanoma cell line, along with superparamagnetic iron oxide nanoparticles, gold nanorods, and Chinese ink nanoparticles can reach the meningeal lymphatic vessels and the brain of C57BL/6 mice after administration within the deep cervical lymph nodes post-mortem and in vivo, exclusively through lymphatic structures. The functional anatomy of dural lymphatics has been found to be conserved between mice and humans, suggesting that our findings may have significant implications for advancing targeted drug delivery systems using nanoparticles. Understanding the retrograde transport of nanoparticles through the meningeal lymphatic network could lead to novel therapeutic approaches in nanomedicine, offering new insights into fluid dynamics in both physiological and neuropathological contexts. Further research into this pathway may unlock new strategies for treating neurological diseases or enhancing drug delivery to the brain.

Ultrasonication-mediated synthesis of diblock polymer-based nanoparticles for advanced drug delivery systems: Insights and optimization

Ultrasonication-mediated synthesis of diblock polymer-based nanoparticles for advanced drug delivery systems: Insights and optimization

NIR-activatable nitric oxide generator based on nanoparticles loaded small-molecule photosensitizers for synergetic photodynamic/gas therapy

BackgroundTherapeutic approaches that combine conventional photodynamic therapy (PDT) with gas therapy (GT) to sensitize PDT are an attractive strategy, but the molecular structure design of the complex lacks effective guiding strategies.ResultsHerein, we have developed a nanoplatforms Cy-NMNO@SiO2 based on mesoporous silica materials loaded NIR-activatable small-molecule fluorescent probe Cy-NMNO for the synergistic treatment of photodynamic therapy/gas therapy (PDT/GT) in antibacterial and skin cancer. The theoretical calculation results showed that the low dissociation of N-NO in Cy-NMNO enabled it to dissociate effectively under NIR light irradiation, which is conducive to produce Cy and NO. Cy showed better 1O2 generation performance than Cy-NMNO. The cytotoxicity of Cy-NMNO obtained via the synergistic effect of GT and PDT synergistically enhances the effect of photodynamic therapy, thus achieving more effective tumor treatment and sterilization than conventional PDT. Moreover, the nanoplatforms Cy-NMNO@SiO2 realized efficient drug loading and drug delivery.ConclusionsThis work not only offers a promising approach for PDT-GT synergistic drug delivery system, but also provides a valuable reference for the design of its drug molecules.Graphical