Drug Delivery Research Articles

Phycocyanin/Hyaluronic Acid Microneedle Patches Loaded with Celastrol Nanoparticles for Synergistic Treatment of Diabetic Nephropathy.

Although multifunctional drug delivery systems have shown significant potential in the treatment of diabetic nephropathy (DN), developing an efficient synergistic drug delivery strategy remains a major challenge. The purpose of this paper is to develop a nanoparticle-loaded microneedle (MN) patch transdermal drug delivery system aimed at achieving blood glucose control and reactive oxygen species (ROS) scavenging for the synergistic treatment of DN. MNs are composed of hyaluronic acid and phycocyanin (PC), both exhibiting excellent biocompatibility and degradation properties. Subsequently, insulin and celastrol (CEL)-based nanoparticles were incorporated into the MN to create the transdermal drug delivery platform (MN-IN&NPs). MN-IN&NPs can penetrate through the stratum corneum of skin and reach the dermis layer. Accompanied by the dissolution of MN, PC, insulin, and CEL-based NPs are continuously released. PC possesses anti-inflammatory and antioxidant properties that enable it to scavenge excessive ROS, thereby exerting synergistic effects alongside CEL nanoparticles. Furthermore, MN-IN&NPs significantly enhance drug transdermal delivery efficiency, while prolonging insulin's action duration. Therefore, MN-IN&NPs effectively integrate blood glucose control with ROS scavenging functions, presenting a promising therapeutic strategy for DN.

A core-shell microneedle system for stable fibroblast delivery in cell-based therapies.

Human cells, such as fibroblasts and particularly human mesenchymal stem cells (hMSCs), represent a promising and effective therapeutic tool for a range of cell-based therapies used to treat various diseases. The effective delivery of therapeutic cells remains a challenge due to limitations in targeting, invasiveness, and cell viability. To address these challenges, we developed a microneedle (MN) system for minimally invasive cell delivery with high cellular stability. The MN system comprises a core of gelatin methacryloyl (GelMA) hydrogel embedded with fibroblasts, encased in a polylactic-co-glycolic acid (PLGA) shell that enhances structural integrity for efficient skin penetration. The fabrication process involves UV-crosslinking of the GelMA hydrogel with cells, optimizing both cell encapsulation and structural strength. This MN system achieves over 80% cell viability after seven days in vitro, with the conventional GelMA formulation providing superior stability and cellular outcomes. This platform's ability to ensure sustained cell viability presents promising implications for future applications in regenerative medicine, wound healing, and localized treatments for skin conditions. This MN system opens new avenues for cell-based therapies, offering a versatile and scalable solution for therapeutic cell delivery.

Cytotoxic effects of bee venom-loaded ZIF-8 nanoparticles on thyroid cancer cells: a promising strategy for targeted therapy.

Thyroid cancer continues to be a notable health issue, requiring the creation of novel treatment methods to enhance patient results. The objective of this study is to investigate the potential of utilizing bee venom (BV)-loaded zeolitic imidazolate framework-8 (ZIF-8) nanoparticles as a novel strategy for specifically targeting and treating medullary thyroid cancer cells. Due to their wide surface area and configurable pore size, ZIF-8 nanoparticles are ideal for drug delivery. Bee venom's cytotoxic capabilities are used in ZIF-8 nanoparticles to target thyroid cancer cells more effectively. ZIF-8 nanoparticles containing bee venom were tested on TT medullary thyroid cancer cell lines. The effects of these nanoparticles on cell viability, proliferation, and apoptosis were investigated. IC50 value at 24h for BV-ZIF-8 nanoparticles in TT medullary thyroid carcinoma cells was determined to be 17.19µg/mL, while the IC50 value at 48h was determined to be 16.39µg/mL. It has been demonstrated that nanoparticle treatment upregulates the Bax and caspase-3 genes while downregulating the Bcl-2, CCND1, and CDK4 genes. Additionally, it was observed that oxidative stress was triggered in the nanoparticle-treated group. Furthermore, an examination of its mechanisms was conducted, with a specific emphasis on the modulation of critical signaling pathways that are implicated in the progression of cancer. In thyroid cancer cells, ZIF-8 nanoparticles infused with bee venom promote programmed cell death and impair key biological processes.

Hydrogel-Assisted Robust Supraparticles Evolved from Droplet Evaporation.

Supraparticles, formed through the self-assembly of nanoparticles, are promising contenders in catalysis, sensing, and drug delivery due to their exceptional specific surface area and porosity. However, their mechanical resilience, especially in dimensions spanning micrometers and beyond, is challenged by the inherently weak interactions among their constituent building blocks, significantly constraining their broad applicability. Here, we have exploited a robust supraparticle fabrication strategy by integrating hydrogel components into the assembly system and evaporating on the superamphiphobic surface. The resultant SiO2/SA (sodium alginate) supraparticles, achieved by evaporating a 15% volume fraction dispersion of SiO2 nanoparticles containing 18.46 mg/mL of sodium alginate and subsequently cross-linking with Ca2+, demonstrate mechanical robustness with a fracture force of 6.04 N, representing a mechanical strength enhancement of 60 times higher than that prior to the incorporation of the hydrogel component. The supraparticles maintain their original morphology after 30 min of ultrasonic treatment (200 W), demonstrating mechanical stability. This method exhibits generalizability, enabling the customization of supraparticles with various building blocks and hydrogel backbone materials. Based on such a methodology, we have synthesized enzyme-carrying supraparticles, further expanding the potential applications in intricate cascade reactions. The encapsulated glucose oxidase and horseradish peroxidase maintained their inherent reactivity, and such hydrogel-assisted robust supraparticles exhibited exceptional performance in accurate glucose assays, indicating great practical application in biocatalysis.

Programming the Kinetics of Chemical Communication: Induced Fit vs Conformational Selection.

Life on Earth depends on chemical communication and the ability of biomolecular switches to integrate various chemical signals that trigger their activation or deactivation over time scales ranging from microseconds to days. The ability to similarly program and control the kinetics of artificial switches would greatly assist the design and optimization of future chemical and nanotechnological systems. Two distinct structure-switching mechanisms are typically employed by biomolecular switches: induced fit (IF) and conformational selection (CS). Despite 60 years of experimental and theoretical investigations, the kinetic and evolutive advantages of these two mechanisms remain unclear. Here, we have created a simple modular DNA switch that can operate through both mechanisms and be easily tuned and adapted to characterize its thermodynamic and kinetic parameters. We show that the fastest activation rate of a switch occurs when the ligand is able to bind its inactive conformation (IF). In contrast, we show that when the ligand can only bind the active conformation of the switch (CS), its activation rate can be easily programmed over many orders of magnitude by a simple tuning of its conformational equilibrium. We demonstrate the programming ability of both these mechanisms by designing a drug delivery vessel that can be programmed to release a drug over different time scales (>1000-fold). Overall, these findings provide a programmable strategy to optimize the kinetics of molecular systems and nanomachines while also illustrating how evolution may have taken advantage of IF and CS mechanisms to optimize the kinetics of biomolecular switches.

A state-of-the-art review of the recent advances in drug delivery systems for different therapeutic agents in periodontitis.

Periodontitis (PD) is a chronic gum illness that may be hard to cure for a number of reasons, including the fact that no one knows what causes it, the side effects of anti-microbial treatment, and how various kinds of bacteria interact with one another. As a result, novel therapeutic approaches for PD treatment must be developed. Additionally, supplementary antibacterial regimens, including local and systemic medication administration of chemical agents, are necessary for deep pockets to assist with mechanical debridement of tooth surfaces. As our knowledge of periodontal disease and drug delivery systems (DDSs) grows, new targeted delivery systems like extracellular vesicles, lipid-based nanoparticles (NPs), metallic NPs, and polymer NPs have been developed. These systems aim to improve the targeting and precision of PD treatments while reducing the systemic side effects of antibiotics. Nanozymes, photodermal therapy, antibacterial metallic NPs, and traditional PD therapies have all been reviewed in this research. Medicinal herbs, antibiotics, photothermal therapy, nanozymes, antibacterial metallic NPs, and conventional therapies for PD have all been examined in this research. After that, we reviewed the key features of many innovative DDSs and how they worked for PD therapy. Finally, we have discussed the advantages and disadvantages of these DDSs.

Apoptotic body based biomimetic hybrid nanovesicles to attenuate cytokine storms for sepsis treatment

Sepsis is a severe immune response to pathogens that is associated with high mortality rate and a paucity of efficacious treatment options. It is characterized by the hyperactivation of macrophages and the occurrence of cytokine storms. Given the anti-inflammatory properties of M2 macrophages and their derived apoptotic bodies (AB), as well as the specific uptake of these by macrophages, a novel approach was employed to combine AB with artificial liposomes to create apoptotic body based biomimetic hybrid nanovesicles (L-AB). The L-AB effectively inherited “eat me” signaling molecules on the surface of the AB, thereby facilitating their targeted uptake by macrophages in both in vitro and in vivo settings. The administration of L-AB for the delivery of dexamethasone effectively augmented the therapeutic efficacy of the drug, mitigated macrophage hyperactivation and tissue damage in vivo, and consequently enhanced the survival rate of septic mice. Taken together, these findings suggest that the apoptotic body biomimetic nanovesicles may represent a potential drug delivery system capable of specifically targeting macrophages for the treatment of sepsis.

Formation of Nonspherical Cellulose Acetate Microparticles under Microflow.

Nonspherical particles have gained significant interest owing to their unique shapes and large specific surface areas, making them suitable for a wide range of applications, such as drug delivery, catalysis, and adsorption. However, conventional methods for preparing nonspherical particles face certain limitations. In this study, we propose a simple method for fabricating nonspherical cellulose acetate (CA) microparticles using a microfluidic device in which droplets undergo rapid diffusion in a continuous aqueous phase. The influence of variations in the flow rate ratio and continuous phase composition on the dimensionless Péclet number (Pe) within the droplet and shape of the resultant particles is investigated. Pe is critical, because it indicates the balance between polymer diffusion and droplet shrinkage dynamics. Our findings reveal that increasing the flow rate ratio and reducing the methyl acetate concentration in the continuous phase lead to faster droplet shrinkage and an increased Pe. A high Pe (>100) suggests that the reduction of the droplet interface predominates over polymer diffusion, resulting in the formation of a viscous layer near the droplet surface, which subsequently leads to nonspherical particle shapes (such as bowl-like or biconcave structures). In situ time-lapse observations of droplets from the top and side of a microchannel reveal that the formation of a viscous layer near the droplet surface and the deformation of the droplet, influenced by the z-axis location of the droplets during particle formation, ultimately determine the final particle shape. Based on these observations, a linear correlation between the initial conditions, i.e., the Pe and z-axis location at which the viscous layer formed, is established, enabling the prediction of the particle structure. In summary, the present study enhances the understanding of shape control in microfluidic particle formation and offers a novel guideline for the fabrication of spherical and nonspherical particles.

Understanding Bacterial Resistance to Heavy Metals and Nanoparticles: Mechanisms, Implications, and Challenges.

Antimicrobial resistance is a global health problem as it contributes to high mortality rates in several infectious diseases. To address this issue, engineered nanoparticles/nano-formulations of antibiotics have emerged as a promising strategy. Nanoparticles are typically defined as materials with dimensions up to 100nm and are made of different materials such as inorganic particles, lipids, polymers, etc. They are widely dispersed in the environment through various consumer products, and their clinical applications are diverse, ranging from contrast agents in imaging to carriers for gene and drug delivery. Nanoparticles can also act as antimicrobial agents either on their own or in combination with traditional antibiotics to produce synergistic effects, earning them the label of "next-generation therapeutics." They have also shown great effectiveness against multidrug-resistant pathogens responsible for nosocomial infections. However, overexposure or prolonged exposure to sublethal doses of nanoparticles can promote the development of resistance in human pathogens. The resistance can arise from various factors such as genetic mutation, horizontal gene transfer, production of reactive oxygen species, changes in the outer membrane of bacteria, efflux-induced resistance, cross-resistance from intrinsic antibiotic resistance determinants, plasmid-mediated resistance, and many more. Continuous exposure to nanoparticles can also transform an antibiotic-susceptible bacterial pathogen into multidrug resistance. Considering all these, the current review focuses on the mode of action of different heavy metals and nanoparticles and possible mechanisms through which bacteria attain resistance towards these heavy metals and nanoparticles.

Hydration Pattern of Ionic Liquids in the Stabilization of Insulin Dimer: A Computational Perspective

AbstractCholine [Cho]‐based ionic liquids (ILs) are biodegradable and soluble and have shown strong application in the protein stabilization and drug delivery. In this work, the stability of the insulin dimer is investigated in the presence of [Cho]‐based ILs containing three distinct anions (i.e., acetate [OAc], taurate [Tau], and geranate [Ger]). Molecular dynamics (MD) simulations and density functional theory (DFT) calculations explore insulin's stability and structure in the presence of ILs. MD analyses reveal that the insulin dimer is stabilized by non‐covalent interactions, with hydrogen bonds and anions in ILs playing key roles. Among them, [Cho][OAc] ILs show significantly better stabilization than other anions.This is due to the hydration patterns of acetate anion, which can be compared to Hofmeister series and chemical agent effects (i.e., kosmotrope and chaotrope). Further, non‐covalent interactions index and electron density analyses from the atoms‐in‐molecules theory approach are carried out to quantify the strength of non‐covalent interaction in ILs with water clusters (Wn, n = 0–6). Analyses show the significance of water molecules in the stabilization of insulin dimer in the presence of [Cho]‐based ILs. The study elucidates the role of ILs formulation concerning insulin dimers to improve the transdermal and oral drug delivery systems.

Nose-to-Brain Delivery of Biomimetic Nanoparticles for Glioblastoma Targeted Therapy.

Glioblastoma (GBM) is an extremely aggressive form of brain cancer that remains challenging to treat, especially owing to the lack of effective targeting and drug delivery concerns. Due to its anatomical advantages, the nose-to-brain strategy is an interesting route for drug delivery. Nanoengineering has provided technological tools and innovative strategies to overcome biotechnological limitations, which is promising for improving the effectiveness of conventional therapies. Herein, we designed a biomimetic multifunctional nanostructure produced by polymeric poly(d,l-lactic-co-glycolic) acid (PLGA) core loaded with Temozolomide (TMZ) coated with cell membrane isolated from glioma cancer cells. The developed nanostructures (NP-MB) were fully characterized, and their biological performance was investigated extensively. The results indicate that NP-MB could control TMZ release and promote TMZ permeation in the ex vivo nasal porcine mucosa. The higher cytotoxicity of NP-MB in different glioma cell lines, particularly against U251 cells, reinforces their potential for homotypic targeting. The chicken chorioallantoic membrane assay revealed a tumor size reduction and antiangiogenic activity. In vivo biodistribution studies showed that NP-MB effectively reaches the brain following nasal administration. These findings suggest that NP-MB holds promise as a biomimetic nanoplatform for effective targeting and homotypic recognition in GBM therapy with high potential for clinical translation.

Dual-Targeted Drug Delivery to Myeloid Leukemia Cells via Complement- and Transferrin-Based Protein Corona.

Although traditionally regarded as an impediment, the protein corona can facilitate the advancement of targeted drug delivery systems. This study presents an innovative approach for targeting acute myeloid leukemia (AML) using nanoparticles with agglutinated protein (NAPs). Agglutinated transferrin and C3b in NAPs selectively bind to CD71 and CD11b, receptors that are overexpressed on myeloid leukemic cells compared to nonmalignant cells. In vitro, NAPs achieved a 73.9% doxorubicin (DOX) uptake in leukemic cells, compared to 6.19% for the free drug, while significantly reducing off-target accumulation in normal cells from 42.9% to 5.76%. In vivo, the distribution of NAPs correlated to the organ infiltration pattern of leukemic cells. NAPs demonstrated antileukemic activity in both in vitro and in vivo NSG mouse models, inducing cell death via apoptosis and ferroptosis. In conclusion, NAP-mediated targeted drug delivery represents a promising therapeutic strategy for AML, enhancing treatment efficacy and minimizing off-target effects.

Nanotechnology for Healthcare: Plant-Derived Nanoparticles in Disease Treatment and Regenerative Medicine

Nanotechnology has revolutionised biomedical research, offering innovative healthcare solutions. Plant-based nanotechnology is emerging as a sustainable alternative, minimising environmental impacts and enhancing therapeutic effectiveness. This paper explores the potential of plant-derived nanoparticles (PNPs) in medicine, highlighting their biocompatibility, multifunctionality, and eco-friendliness. PNPs, synthesised through green methods, have demonstrated promising applications in drug delivery, cancer therapy, antimicrobial treatments, and tissue regeneration. Their unique properties, such as a high surface area and bioactive components, enable improved drug delivery, targeting, and controlled release, reducing side effects and enhancing treatment efficacy. Additionally, plant-derived compounds’ inherent antimicrobial and antioxidant properties, retained within platinum nanoparticles (PNPs), present innovative opportunities for combating antimicrobial resistance and promoting wound healing. Despite their potential, challenges remain in standardising PNP synthesis, ensuring consistency, and scaling up production for industrial applications. This review emphasises the need for further research on PNP toxicity, biocompatibility, and regulatory frameworks to fully harness their capabilities in clinical and commercial applications. Plant-based nanotechnology represents a promising, greener alternative for advancing healthcare solutions, aligning with global sustainability goals.

Bicontinuous Nanoparticles from Spontaneous Self-Assembly of Block Copolymer Prodrug in Aqueous Medium for Potential Cancer Therapy.

Despite having several advantages, bicontinuously structured polymeric nanoparticles (BSPNPs) are far less explored in the field of controlled drug delivery owing to the requirement of complex precursor copolymers and the associated multistep synthetic procedures. In this work, we report the synthesis of a redox-sensitive diblock copolymer (P1), which was subsequently utilized to prepare doxorubicin (DOX) containing a pH-labile prodrug (P2). P1 and P2 spontaneously self-assembled in aqueous media above their critical aggregation concentration, forming micellar nanoparticles with rare bicontinuous morphology that promotes loading of both hydrophobic and hydrophilic cargoes in different compartments. To the best of our knowledge, the formation of BSPNPs through direct self-assembly in aqueous media has not yet been reported. In vitro cellular studies asserted the higher safety profile of the nanoparticles against noncancerous cells (HEK293T) than free DOX, whereas they displayed higher drug-induced cytotoxicity against cancer cells (MCF-7) in comparison to free DOX, establishing them as promising cancer drug delivery systems.

Thermally Solvent-Free Cross-Linked pH/Thermosensitive Hydrogels as Smart Drug Delivery Systems

An imbalance in the body’s pH or temperature may modify the immune response and result in ailments such as autoimmune disorders, infectious diseases, cancer, or diabetes. Dual pH- and thermo-responsive carriers are being evaluated as advanced drug delivery microdevices designed to release pharmaceuticals in response to external or internal stimuli. A novel drug delivery system formulated as hydrogel was developed by combining a pH-sensitive polymer (the “biosensor”) with a thermosensitive polymer (the delivery component). Thus, the hydrogel was created by cross-linking, using a solvent-free thermal approach, of poly(N-isopropylacrylamide-co-N-hydroyethyl acrylamide), P(NIPAAm-co-HEAAm), and poly(methylvinylether-alt-maleic acid), P(MVE/MA). The chemical structure of the polymers and hydrogels was analyzed using Fourier-transform infrared (FTIR) and proton nuclear magnetic resonance (1H NMR) spectroscopies. The pH/thermosensitive hydrogel loses its thermosensitivity under physiological conditions but, remarkably, can recover the thermosensitive capabilities when certain physiologically active biomolecules, acting as triggering agents, electrostatically interact with pH-sensitive units. Our research aimed to develop a drug delivery system that could identify the disturbance of normal physiological parameters and instantaneously send a signal to thermosensitive units, which would collapse and modulate the release profiles of the drug.

Artificial Nanovesicles Derived from Cells: A Promising Alternative to Extracellular Vesicles.

As naturally secreted vesicles by cells, extracellular vesicles (EVs) play essential roles in modulating cell-cell communication and have significant potential in tissue regeneration, immune regulation, and drug delivery. However, the low yield and uncontrollable heterogeneity of EVs have been obstacles to their widespread translation into clinical practice. Recently, it has been discovered that artificial nanovesicles (NVs) produced by cell processing can inherit the components and functions of the parent cells and possess similar structures and functions to EVs, with significantly higher yields and more flexible functionalization, making them a powerful complement to natural EVs. This review focuses on recent advances in the research of artificial NVs as replacements for natural EVs. We provide an overview comparing natural EVs and artificial NVs and summarize the top-down preparation strategies of NVs. The applications of NVs prepared from stem cells, differentiated cells, and engineered cells are presented, as well as the latest advances in NV engineering. Finally, the main challenges of artificial NVs are discussed.

Actuation-Mediated Compression of a Mechanoresponsive Hydrogel by Soft Robotics to Control Release of Therapeutic Proteins.

Therapeutic proteins, the fastest growing class of pharmaceuticals, are subject to rapid proteolytic degradation in vivo, rendering them inactive. Sophisticated drug delivery systems that maintain protein stability, prolong therapeutic effects, and reduce administration frequency are urgently required. Herein, a mechanoresponsive hydrogel is developed contained within a soft robotic drug delivery (SRDD) device. In a step-change from previously reported systems, pneumatic actuation of this system releases the cationic therapeutic protein Vascular Endothelial Growth Factor (VEGF) in a bioactive form which is required for therapeutic angiogenesis, the growth of new blood vessels, in numerous clinical conditions. The ability of the SRDD device to release bioactive VEGF in a spatiotemporal manner from the hydrogel is tested in diabetic rats - a model in which angiogenesis is difficult to stimulate. Daily actuation of the SRDD device in the diabetic rat model significantly increased cluster of differentiation 31+ (CD31+) blood vessel number (p=0.0335) and the diameter of alpha-smooth muscle actin+ (α-SMA+) blood vessels (p=0.0025) compared to passive release of VEGF from non-actuated devices. The SRDD device combined with the mechanoresponsive hydrogel offers the potential to deliver an array of bioactive therapeutics in a spatiotemporal manner to mimic their natural release in vivo.

Polymeric Nanodiscs Comprising 5-Fluorouracil for Inhibition of Protein Aggregation and Their Anti-Alzheimer's Activity in the Drosophila Model.

Nanoconjugates are promising for therapeutic drug delivery and targeted applications due to the numerous opportunities to functionalize their surface. The present study reports the synthesis of 5-fluorouracil (5-FU)-entrapped polyvinylpyrrolidone (PVP) nanoconjugates, precisely 5-FU-PVP and 5-FU-PVP-Au, and the evaluation of protein aggregation inhibition efficiency. The 5-FU-loaded polymer nanoconjugates were functionalized with gold nanoparticles and analyzed using characterization techniques like dynamic light scattering, UV-visible spectroscopy, Fourier-transform infrared spectroscopy, and zeta potential analysis. These conjugates exhibit consistent morphology with a spherical, flat, disc-like structure. The 5-FU-PVP and 5-FU-PVP-Au nanoconjugates exhibited a high drug loading, up to 81% and 90%, respectively. The nanoconjugates exhibited prolonged drug delivery of 5-FU from 5-FU-PVP and 5-FU-PVP-Au, wherein 5-FU-PVP-Au depicted a higher drug release. They were investigated for inhibiting the protein hen egg white lysozyme (HEWL) aggregation by ThT fibril size measurement, binding assay, and electron microscopy, and the results showed that conjugates repressed the fibrillogenesis in HEWL. The prominent activity of amyloid aggregation inhibition for HEWL using 5-FU-PVP and 5-FU-PVP-Au was found to be 29 μg.mL-1 and 27 μg.mL-1, respectively. The dissociation of amyloid aggregates was achieved against 5-FU-PVP and 5-FU-PVP-Au at 27 μg.mL-1 and 25 μg.mL-1, respectively. Furthermore, the nanoconjugates were investigated for anti-Alzheimer's activity in the Drosophila model. A Drosophila model of Alzheimer's disease (AD) was developed that expressed Aβ42 peptides in the neuronal secretory system to comprehend the pathogenic effects of Aβ42 in vivo. All the results demonstrate that polymer nanoconjugates exhibit more effective inhibition of protein aggregation than bare drugs.

Targeting breast tumor extracellular matrix and stroma utilizing nanoparticles.

Breast cancer is a complicated malignancy and is known as the most common cancer in women. Considerable experiments have been devoted to explore the basic impacts of the tumor stroma, particularly the extracellular matrix (ECM) and stromal components, on tumor growth and resistance to treatment. ECM is made up of an intricate system of proteins, glycosaminoglycans, and proteoglycans, and maintains structural support and controls key signaling pathways involved in breast tumors. ECM can block different drugs such as chemotherapy and immunotherapy drugs from entering the tumor stroma. Furthermore, the stromal elements, such as cancer-associated fibroblasts (CAFs), immune cells, and blood vessels, have crucial impacts on tumor development and therapeutic resistance. Recently, promising outcomes have been achieved in using nanotechnology for delivering drugs to tumor stroma and crossing ECM in breast malignancies. Nanoparticles have various benefits for targeting the breast tumor stroma, such as improved permeability and retention, extended circulation time, and the ability to actively target the area. This review covers the latest developments in nanoparticle therapies that focus on breast tumor ECM and stroma. We will explore different approaches using nanoparticles to target the delivery of anticancer drugs like chemotherapy, small molecule drugs, various antitumor products, and other specific synthetic therapeutic agents to the breast tumor stroma. Furthermore, we will investigate the utilization of nanoparticles in altering the stromal elements, such as reprogramming CAFs and immune cells, and also remodeling ECM.

Three-Dimensional Printing of Hydrogel Blend Tissue Engineering Scaffolds with In Situ Delivery of Anticancer Drug for Treating Melanoma Resection-Induced Tissue Defects

Surgery is considered the gold standard for treating melanoma, but the high recurrence rate after surgery still remains as a major challenge. Therefore, using doxorubicin (DOX) as a model drug, this study investigated the 3D printing of anticancer drug-loaded hydrogel blend scaffolds for inhibiting post-operation melanoma recurrence and for promoting tissue regeneration. Three-dimensional printing could successfully produce methacrylate-modified chitosan (CSMA) and methylcellulose (MC) hydrogel blend scaffolds. Polymer blend inks exhibited satisfactory printability, and the printed porous scaffolds showed good biocompatibility and mechanical properties. Three-dimensionally printed DOX-loaded hydrogel scaffolds displayed controlled drug release, which may effectively prevent/impede tumor recurrence after surgery. Furthermore, combining 3D printing and bioprinting, DOX-loaded and rat bone marrow mesenchymal stem cell (rBMSC)-laden scaffolds were created for assessing local DOX delivery on healthy tissues. Within the 14-day culture period, rBMSCs encapsulated in multilayered scaffolds that were incorporated with DOX displayed rejuvenated cell viability. The 3D printed and bioprinted dual purpose hydrogel scaffolds have the promise of combating tumor recurrence and providing structural support for tissue regeneration.