Polymeric Micelles Research Articles

Hybrid Microneedle-Mediated Transdermal Delivery of Atorvastatin Calcium-Loaded Polymeric Micelles for Hyperlipidemia Therapy.

Hyperlipidemia has been a huge challenge to global health, leading to the cardiovascular disease, hypertension, and diabetes. Atorvastatin calcium (AC), a widely prescribed drug for hyperlipidemia, faces huge challenges with oral administration due to poor water solubility and hepatic first-pass effects, resulting in low therapeutic efficacy. In this work, we designed and developed a hybrid microneedle (MN) patch system constructed with soluble poly(vinyl alcohol) (PVA) and AC-loaded polymeric micelles (AC@PMs) for transdermal delivery of AC to enhance the hyperlipidemia therapy. We first prepared various AC@PM formulations self-assembled from mPEG-PLA and mPEG-PLA-PEG block copolymers using a dialysis method and evaluated the physicochemical properties in combination with experiment skills and dissipative particle dynamics (DPD) simulations. Then, we encapsulated the AC@PMs into the PVA MN patch using a micromold filling method, followed by characterizing the performances, especially the structural stability, mechanical performance, and biosafety. After conducting in vivo experiments using a hyperlipidemic rat model, our findings revealed that the hybrid microneedle-mediated administration exhibited superior therapeutic efficacy when compared to oral delivery methods. In summary, we have successfully developed a hybrid microneedle (MN) patch system that holds promising potential for the efficient transdermal delivery of hydrophobic drugs.

Functionalized nanoparticles to deliver nucleic acids to the brain for the treatment of Alzheimer’s disease

Brain-targeted gene delivery across the blood-brain barrier (BBB) is a significant challenge in the 21st century for the healthcare sector, particularly in developing an effective treatment strategy against Alzheimer’s disease (AD). The Internal architecture of the brain capillary endothelium restricts bio-actives entry into the brain. Additionally, therapy with nucleic acids faces challenges like vulnerability to degradation by nucleases and potential immune responses. Functionalized nanocarrier-based gene delivery approaches have resulted in safe and effective platforms. These nanoparticles (NPs) have demonstrated efficacy in protecting nucleic acids from degradation, enhancing transport across the BBB, increasing bioavailability, prolonging circulation time, and regulating gene expression of key proteins involved in AD pathology. We provided a detailed review of several nanocarriers and targeting ligands such as cell-penetrating peptides (CPPs), endogenous proteins, and antibodies. The utilization of functionalized NPs extends beyond a singular system, serving as a versatile platform for customization in related neurodegenerative diseases. Only a few numbers of bioactive regimens can go through the BBB. Thus, exploring functionalized NPs for brain-targeted gene delivery is of utmost necessity. Currently, genes are considered high therapeutic potential molecules for altering any disease-causing gene. Through surface modification, nanoparticulate systems can be tailored to address various diseases by replacing the target-specific molecule on their surface. This review article presents several nanoparticulate delivery systems, such as lipid NPs, polymeric micelles, exosomes, and polymeric NPs, for nucleic acids delivery to the brain and the functionalization strategies explored in AD research.

Hybrid copper-polyelectrolyte nanoaggregates obtained with smart block copolymers based on 4-[(hydroxyimino)aldehyde]butyl methacrylate (HIABMA) in water and acetonitrile

The AB multi-stimuli-responsive block copolymer pTEGMA-b-pHIABMA (TEGMA: tetra(ethyleneglycol) methyl ether methacrylate; HIABMA: 4-[(hydroxyimino)aldehyde]butyl methacrylate) comprises a hydrophilic and thermoresponsive PTEGMA block linked to the hydrophobic PHIABMA chain. The latter is endowed with slightly acidic oxime groups that potentially form complexes with metal ions. Here we investigate the formation of hybrid Cu(II)-polymer nanoaggregates both in water and in acetonitrile. Cu(II) ions are quantitatively and rapidly incorporated, in the presence of a base, into pre-formed polymeric core-shell micelles (30 nm diameter by DLS) in water up to 1:2 metal-to-ligand stoichiometry. The pKa of the polymer is decreased from ≅11.2 to 4.65 due to interaction with Cu(II) and the complex is shown to involve oximate ions. The thermoresponsivity of the polymeric micelles remains unchanged with Cu(II) complexation and allows an easy separation by flocculation of the hybrid complex. Moreover, nanoaggregates (D = 20 nm) form in acetonitrile from the fully solubilized copolymer interacting with Cu(OAc)2. The 1:2 Cu(II)/ligand stoichiometry is confirmed with the Job graphical method. Characterization of the hybrid micelles was carried out by UV–Vis spectrometry, DLS, TEM, STEM and SAXS. Quantitative release of Cu(II) in acidic conditions is demonstrated both in water and in acetonitrile. Full recovery of the free metal ions and of intact polymeric micelles is achieved through centrifugal filtration of the aqueous preparation, as a proof-of-concept for a recyclable system for metal uptake and release. Furthermore, Cu0 nanoparticles of 5–10 nm are obtained through reduction of Cu(II) within the micelles with ascorbic acid in aqueous solution.

Anti-Inflammatory Potential of Beclometasone-Loaded Filomicelles on Activated Human Monocytes.

Polymeric micelles with a hydrophobic core represent versatile nanostructures for encapsulation and delivery of water-insoluble drugs. Here, water-insoluble beclometasone dipropionate (BDP) which is a potent anti-inflammatory therapeutic agent but limited to topical applications so far, is encapsulated. Therefore, this work used an amphiphilic block copolymer self-assembling into flexible polymeric filomicelles, which have recently proven to selectively target inflamed areas in patients with inflammatory bowel disease (IBD). The small diameter and flexibility of these filomicelles is considered beneficial for transepithelial passages, while their length minimizes the unspecific uptake into nontargeted cells. This work successfully establishes a protocol to load the water-insoluble BDP into the core of the filomicelles, while maintaining the particle stability to prevent any premature drug release. The anti-inflammatory efficacy of BDP-loaded filomicelles is further investigated on lipopolysaccharide (LPS) stimulated human monocytes. In these ex vivo assays, the BDP-loaded filomicelles significantly reduce TNF-α, IL-6, IL-1ß, IL-12p70, IL-17a, and IL-23 release after 24 h. Additional time course study of drug-loaded filomicelles and their comparison with a common water-soluble and unspecific corticosteroid demonstratepromising results with significant immune response suppression in stimulated monocytes after 2 and 6 h. These findings demonstrate the potential of polymeric filomicelles as a vehicle for potent water-insoluble corticosteroids.

Exploring pectin-casein micelles as novel carriers for oral drug delivery of artesunate in the treatment of systemic lupus erythematosus

The oral route of administration is considered the optimal choice for treating chronic diseases due to its convenience and non-invasiveness, which can help prevent physical and mental harm to patients undergoing long-term treatment. However, challenges such as safety, gastrointestinal stability, and bioavailability of oral drugs often limit their effectiveness. Natural biomacromolecule micelles, known for their safety, stability, biocompatibility, and diverse functions, have emerged as promising carriers for oral treatment of chronic diseases like systemic lupus erythematosus (SLE) with fat-soluble drugs. This study introduces an innovative approach by developing an oral delivery system using chemically synthesized natural biomacromolecules to load artesunate for treating SLE. By synthesizing amphiphilic polymer micelles from pectin and casein through a carbodiimide reaction, a more stable structure is achieved. The hydrophobic core of these micelles encapsulates artesunate, resulting in the formation of an oral delivery system (PC-AS) with several advantages, including high drug loading and encapsulation efficiency, small particle size, negative potential, strong stability in the gastrointestinal tract, low toxicity and side effects, strong adhesion in the small intestine, and high bioavailability. These advantages facilitate efficient absorption of artesunate in the gastrointestinal tract, leading to improved bioavailability and effective alleviation of SLE-like symptoms in MRL/lpr mice. By utilizing chemically synthesized natural macromolecular micelles for delivering artesunate in the treatment of SLE, this study overcomes the oral barriers associated with the original drug and presents a novel solution for the long-term oral treatment of chronic diseases.

Recent Advances and Clinical Approach to Cancer Treatment with Nanotechnology Derived Biomolecule.

Cancer nanomedicine has the potential to take advantage of the multifunctionality and diverse biological activity of nanostructures based on biomolecules. Novel drug delivery vehicles can be designed by programming the supramolecular features of biomolecules to achieve multiple therapeutic goals at once, including efficient in vivo transport and targeted drug administration. Proteins, peptides, nucleic acids, and polysaccharides can all be engineered into multipurpose nanomedicines. Even while numerous cancer medications reduce mortality, they are still insufficient. Early cancer cell detection and high-specificity therapeutic administration optimise treatment and prevent toxicity. Nanotechnology is improving cancer diagnosis and treatment due to increased systemic toxicity and refractoriness with current methods. Nanotechnology-based immunotherapeutic drugs have reduced cancer cell invasiveness while protecting healthy cells in several cancer types. Carbon nanotubes, polymeric micelles, and liposomes improve cancer medication pharmacokinetics and pharmacodynamics. Nanomedicines' use in patient care and promising nanotechnology-based cancer interventions have been covered in this article. Nanomaterials used in treating cancer have been discussed. Additionally, nanomaterial obstacles that hinder their applicability and clinical translation in certain cancer types are addressed.

Celastrol-loaded polymeric mixed micelles shows improved antitumor efficacy in 4 T1 bearing xenograft mouse model through spatial targeting

In this study, we have proposed a novel approach that combines hyaluronic acid (HA), folic acid (FA), and celastrol (CLS) within a polymeric micelle system (CLS-HF/MLs), offering a dual-action strategy against breast cancer. Polymeric mixed micelles were prepared through the thin-film hydration method, and comprehensive quality control parameters were established, encompassing particle size, polydispersity index, zeta potential, surface morphology, encapsulation efficiency, drug content, in vitro drug release, and storage stability assessment. The average particle size of CLS-HF/MLs micelles was found to be 120 nm and their drug loading and encapsulation efficiencies were 15.9 % and 89.52 %, respectively. The in vitro release data showed that the CLS-HF/MLs targeted mixed micelles displayed a prolonged release profile compared to the free drug. Additionally, the stability of the developed polymeric mixed micelles was maintained for up to 8 weeks of storage in terms of particle size and drug content. Furthermore, both flow cytometry and confocal laser scanning microscopy studies indicated a significant enhancement in the cellular uptake efficiency and cytotoxicity of CLS-HF/MLs mixed micelles against MCF-7 cell line. In terms of pharmacokinetic analysis, the half-life and AUC values of CLS-HF/MLs mixed micelles were found to be approximately 4.71- and 7.36-folds higher than the values of free drug (CLS), respectively. The CLS-HF/MLs micelles exhibited remarkable antitumor efficacy (almost complete ablation of the 4 T1-cell bearing tumor xenografts mouse model) due to the dual receptor (CD44 and folate) targeting effects with minimal side effects. When considering the cumulative findings of our present research, it becomes evident that mixed micelles designed for chemotherapy offer a promising and potentially effective therapeutic avenue for the treatment of breast cancer

Development of xylan-coated acid-resistant micellar drug carriers for colon-targeted oral delivery

Oral delivery of hydrophobic drugs from the stomach through the colon has some requirements: (1) an acid-resistant carrier (2) a colon-specific drug release mechanism; and (3) an enhanced bioavailability. In this study, curcumin-loaded polymeric micelles with a xylan-based composite coating were designed and developed. For this purpose, a new synthesis method was used to precipitate xylan by concurrent chitosan polymerization at different xylan/chitosan ratios using a negatively charged crosslinking agent, TPP. The study was to provide the stability of the coated micellar structures in the stomach (low pH conditions) and their degradation in the colon (a natural environment of bacteria) to release the drug. It was observed that the coating successfully prevented early drug release up to 85%, depending on the fraction of xylan in the coating. The nanocarriers that first passed through the stomach conditions were incubated with a xylanolytic colonic bacterium (Bacteroides ovatus) to determine the bacterium-related release mechanism, which was around 27%. This shows the colon-specific release expectation of coated nanocarriers in the colon environment, with an additional benefit due to the degradation of xylan and an improvement in the colon environment by prebiotic activity.

A broadly applicable protein-polymer adjuvant system for antiviral vaccines

Although protein subunit vaccines generally have acceptable safety profiles with precise antigenic content, limited immunogenicity can lead to unsatisfactory humoral and cellular immunity and the need for vaccine adjuvants and delivery system. Herein, we assess a vaccine adjuvant system comprising Quillaja Saponaria-21(QS-21) and cobalt porphyrin polymeric micelles that enabling the display of His-tagged antigen on its surface. The nanoscale micelles promote antigen uptake and dendritic cell activation to induce robust cytotoxic T lymphocyte response and germinal center formation. Using the recombinant protein antigens from influenza A and rabies virus, the micelle adjuvant system elicited robust antiviral responses and protected mice from lethal challenge. In addition, this system could be combined with other antigens to induce high titers of neutralizing antibodies in models of three highly pathogenic viral pathogens: Ebola virus, Marburg virus, and Nipah virus. Collectively, our results demonstrate this polymeric micelle adjuvant system can be used as a potent nanoplatform for developing antiviral vaccine countermeasures that promote humoral and cellular immunity.

Reactive oxygen species-responsive supramolecular deucravacitinib self-assembly polymer micelles alleviate psoriatic skin inflammation by reducing mitochondrial oxidative stress.

The new topical formula is urgent needed to meet clinical needs for majority mild patients with psoriasis. Deucravacitinib exerts outstanding anti-psoriatic capacity as an oral TYK2 inhibitor; however, single therapy is insufficient to target the complicated psoriatic skin, including excessive reactive oxygen species (ROS) and persistent inflammation. To address this need, engineered smart nano-therapeutics hold potential for the topical delivery of deucravacitinib. hydrophobic Deucravacitinib was loaded into polyethylene glycol block-polypropylene sulphide (PEG-b-PPS) for transdermal delivery in the treatment of psoriasis. The oxidative stress model of HaCaT psoriasis was established by TNF-α and IL-17A in vitro. JC-1 assay, DCFH-DA staining and mtDNA copy number were utilized to assess mitochondrial function. 0.75% Carbopol®934 was incorporated into SPMs to produce hydrogels and Rhb was labeled to monitor penetration by Immunofluorescence. In vivo, we established IMQ-induced psoriatic model to evaluate therapeutic effect of Car@Deu@PEPS. Deu@PEPS exerted anti-psoriatic effects by restoring mitochondrial DNA copy number and mitochondrial membrane potential in HaCaT. In vivo, Car@Deu@PEPS supramolecular micelle hydrogels had longer retention time in the dermis in the IMQ-induced ROS microenvironment. Topical application of Car@Deu@PEPS significantly restored the normal epidermal architecture of psoriatic skin with abrogation of splenomegaly in the IMQ-induced psoriatic dermatitis model. Car@Deu@PEPS inhibited STAT3 signaling cascade with a corresponding decrease in the levels of the differentiation and proliferative markers Keratin 17 and Cyclin D1, respectively. Meanwhile, Car@Deu@PEPS alleviated IMQ-induced ROS generation and subsequent NLRP3 inflammasome-mediated pyroptosis. Deu@PEPS exerts prominent anti-inflammatory and anti-oxidative effects, which may offers a more patient-acceptable therapy with fewer adverse effects compared with oral deucravacitinib.

A Systematic Study on the Physicochemical Interactions Between Polymeric Micelles and Mucin: Toward the Development of Optimal Drug Delivery Nanocarriers

AbstractThe optimal performance of drug delivery formulations, including polymeric nanoparticles, relies on particle distribution throughout the body and the interactions with biological barriers, particularly mucosal layers, which often limit their potential. A systematic and comprehensive study is presented through a multidisciplinary approach combining conventional and novel techniques for in vitro studies to understand the key molecular interactions between polymeric micelles and mucin. The results shows that polymeric micelles are integrates within the mucin layer, mirroring its viscoelastic properties, evidenced as a dissipation difference of 0.1 ± 0.44, measured by quartz crystal microbalance with dissipation. Surface‐enhanced Raman scattering reveals predominant hydrogen bonding within the mucin's hydrophilic core, while the isothermal titration calorimetry method confirms multiple non‐specific binding sites on the protein backbone. By performing the periodic acid‐Schiff stain assay, a binding amount of 0.20 mg of mucin per milligram of nanoparticles is quantified. Furthermore, motility studies show the surface binding of mucin on the polymeric nanoparticles influencing their Brownian motion. This study sheds light toward the improvement for a better drug delivery formulation and fabrication of optimal nanoparticle colloidal systems, which can advance translational drug delivery technologies into clinical application while enriching the field of surface and colloidal chemistry.

Using Poly(N‐isopropylacrylamide) and Poly(ethyleneglycol) Grafted Polycarbodiimides as Unique Nanocarriers for Hydrophobic Form of the Doxorubicin (DOX)

AbstractAmphiphilic helical polycarbodiimides bearing side chains with terminal alkyne groups provide a unique platform for construction of polymeric micelles. Incorporation of propargyl pendants into polyguanidine backbone allowed post‐polymerization modification with azide terminated, random coil, poly(N‐isopropylacrylamide), PNIPAM15K and poly(ethyleneglycol), PEG2K moieties using copper‐catalyzed click reaction (CuAAC). Thus, four new amphiphilic brush copolymers with varying grafting density were synthesized and their self‐assembly behavior in aqueous medium was studied by combination of TEM, SEM, AFM, and optical microscopy techniques. It was shown the formation of micellar structures at critical micelle concentration (CMC) ranging from 1.58 × 10−5 to 1.05 × 10−3mg mL−1. A hydrophobic drug doxorubicin (DOX) was then encapsulated successfully into these micellar structures with encapsulation efficiency (EE) falling in the range from 16% to 27%. Further, the cellular uptake studies were carried out by using HeLa cells and the cytotoxic activity of DOX‐loaded micelles was determined to be less than 65% of cell viability at a concentration of 0.250 mg mL−1. Fluorescence microscopy imaging revealed importing the micelles into the cells by endocytosis and internalization of the DOX into nucleus of the HeLa cells.

Pegylated polymeric micelles of boswellic acid-selenium mitigates repetitive mild traumatic brain injury: Regulation of miR-155 and miR-146a/BDNF/ Klotho/Foxo3a cue

This study aims to explore the protective machinery of pegylated polymeric micelles of boswellic acid-selenium (PMBS) against secondary neuronal damage triggered by mild repetitive traumatic brain injury (RTBI). After PMBS characterization in terms of particle size, size distribution, zeta potential, and transmission electronic microscopy, the selected formula was used to investigate its potency against experimental RTBI. Five groups of rats were used; group 1 (control) and the other four groups were subjected to RTBI. Groups 2 was RTBI positive control, while 3, 4, and 5 received boswellic acid (BSA), selenium (SEL), and PMBS, respectively. The open-field behavioral test was used for behavioral assessment. Subsequently, brain tissues were utilized for hematoxylin and eosin staining, Nissl staining, Western blotting, and ELISA in addition to evaluating microRNA expression (miR-155 and miR-146a). The behavioral changes, oxidative stress, and neuroinflammation triggered by RTBI were all improved by PMBS. Moreover, PMBS mitigated excessive glutamate-induced excitotoxicity and the dysregulation in miR-155 and miR-146a expression. Besides, connexin43 (Cx43) expression as well as klotho and brain-derived neurotrophic factor (BDNF) were upregulated with diminished neuronal cell death and apoptosis because of reduced Forkhead Box class O3a(Foxo3a) expression in the PMBS-treated group. The current study has provided evidence of the benefits produced by incorporating BSA and SEL in PEGylated polymeric micelles formula. PMBS is a promising therapy for RTBI. Its beneficial effects are attributed to the manipulation of many pathways, including the regulation of miR-155 and miR-146a expression, as well as the BDNF /Klotho/Foxo3a signaling pathway.

Tailoring micellar nanocarriers for pemetrexed in breast cancer: design, fabrication and in vitro evaluation.

Aim: To investigate the pemetrexed encapsulated polymeric mixed micelles (PMMs) against breast cancer treatment.Methods: We meticulously optimized the formulation and conducted extensive characterizations, including photon correlation spectroscopy for micellization, advanced analytical techniques and in vitro cell line assessments.Results: The PMM exhibited favorable characteristics, with a spherical morphology, hydrodynamic particle size of 19.58±0.89nm, polydispersity index of 0.245±0.1, and a surface charge of -9.70±0.61mV. Encapsulation efficiency and drug payload reached 96.16±0.37% and 4.5±0.32%, respectively. Cytotoxicity analysis indicated superior efficacy of the PMM over the drug solution.Conclusion: The PMM formulation exhibited controlled release of the drug, and demonstrated enhanced cytotoxicity against breast cancer cells, highlighting its therapeutic promise.

Investigation of morphology and structure of drug-loaded PLA-b-PEO-b-PLA polymeric micelle: A dissipative particle dynamics simulations study.

The dissipative particle dynamics (DPD) simulation was used to study the morphologies and structures of the paclitaxel-loaded PLA-b-PEO-b-PLA polymeric micelle. We focused on the influences of PLA block length, PLA-b-PEO-b-PLA copolymer concentration, paclitaxel drug content on morphologies and structures of the micelle. Our simulations show that: (i) with the PLA block length increase, the self-assemble structure of PLA-b-PEO-b-PLA copolymers with paclitaxel vary between onion-like structure (core-middle layer-shell) to spherical core-shell structure. The PEO shell thins and the size of the PLA core increases. The onionlike structures are comprised of the PEO hydrophilic core, the PLA hydrophobic middle layer, and the PEO hydrophilic shell, the distribution of the paclitaxel drug predominantly occurs within the hydrophobic intermediate layer; (ii) The system forms a spherical core-shell structure when a small amount of the drug is added, and within a certain range, the size of the spherical structure increases as the drug amount increases. When the drug contents (volume fraction) cdrug = 10%, it can be observed that the PLA4-b-PEO19-b-PLA4 spherical structures connect to form rod-shaped structures. With the length of PLA block NPLA = 8, as the paclitaxel drug concentrations cdrug = 4%, PEO has been insufficient to completely encapsulate the PLA and paclitaxel drug beads. To enhance drug loading capacity while maintaining stability of the system in aqueous solution, the optimal composition for loading paclitaxel is PLA4-b-PEO19-b-PLA4; the drug content is not higher than 4%; (iii) The paclitaxel-loaded PLA4-b-PEO19-b-PLA4 micelle undergo the transition from onionlike (core-middle layer-shell) to spherical (core-shell) to rod-shaped and lamellar structure as the PLA4-b-PEO19-b-PLA4 copolymer concentration increases from ccp = 10% to 40%.

Polymer Conjugate as the New Promising Drug Delivery System for Combination Therapy against Cancer.

This review highlights the advantages of combination therapy using polymer conjugates as drug delivery systems for cancer treatment. In this review, the specific structures and materials of polymer conjugates, as well as the different types of combination chemotherapy strategies, are discussed. Specific targeting strategies, such as monoclonal antibody therapy and small molecule ligands, are also explored. Additionally, self-assembled polymer micelles and overcoming multidrug resistance are described as potential strategies for combination therapy. The assessment of combinational therapeutic efficacy and the challenges associated with polymer conjugates are also addressed. The future outlook aims to overcome these challenges and improve the effectiveness of drug delivery systems for combination therapy. The conclusion emphasizes the potential of polymer conjugates in combination therapy while acknowledging the need for further research and development in this field.

Selective Uptake Into Inflamed Human Intestinal Tissue and Immune Cell Targeting by Wormlike Polymer Micelles (Small 21/2024)

Selective Uptake Into Inflamed Human Intestinal Tissue and Immune Cell Targeting by Wormlike Polymer Micelles (Small 21/2024)

Impact of Zwitterions on the Acidity Constant and Glucose Sensitivity of Block Copolymers with Phenylboronic Acid.

Molecular assemblies that transform in response to pH and saccharide concentration are promising nanomaterials in the field of biomedicine, and polymeric micelles of amphiphilic polymers with phenylboronic acids (PBAs) have been studied. Herein, we report the impact of zwitterions on the acidity constant for the collapse and the glucose sensitivity of a polymeric micelle produced from a diblock copolymer comprising polyacrylamides with PBA and zwitterionic carboxybetaine (PAEBB-b-PCBAAm). The diblock copolymer was synthesized through reversible addition-fragmentation chain-transfer polymerization followed by deprotection. PAEBB-b-PCBAAm produced micellar aggregates in aqueous solutions at a neutral pH, and the polymeric micelles collapsed at a pH of 11.0 because the PBA transformed into a hydroxyboronate anion. The pKa decreased in the presence of glucose owing to boronate ester formation. The PCBAAm chain significantly increased the pH at which the molecular assemblies dissociated. This is probably because the pKa of boronic acid increased through the dipolar interaction of zwitterions, and/or the zwitterionic polymer corona is valid for screening of PBA ionization and electrostatic repulsion of boronate anions. This study on the modulation of pKa through the zwitterionic interaction can facilitate the molecular design of pH- and saccharide-responsive biomaterials.

Hierarchical Design of Tissue-Mimetic Fibrillar Hydrogel Scaffolds.

Most tissues of the human body present hierarchical fibrillar extracellular matrices (ECMs) that have a strong influence over their physicochemical properties and biological behavior. Of great interest is the introduction of this fibrillar structure to hydrogels, particularly due to the water-rich composition, cytocompatibility, and tunable properties of this class of biomaterials. Here, the main bottom-up fabrication strategies for the design and production of hierarchical biomimetic fibrillar hydrogels and their most representative applications in the fields of tissue engineering and regenerative medicine are reviewed. For example, the controlled assembly/arrangement of peptides, polymeric micelles, cellulose nanoparticles (NPs), and magnetically responsive nanostructures, among others, into fibrillar hydrogels is discussed, as well as their potential use as fibrillar-like hydrogels (e.g., those from cellulose NPs) with key biofunctionalities such as electrical conductivity or remote stimulation. Finally, the major remaining barriers to the clinical translation of fibrillar hydrogels and potential future directions of research in this field are discussed.

Dual-modified brain-targeting lipid polymer micelle delivery of anti-miRNA-21 for achieving oral treatment of glioma

Glioma represents a predominant intracranial malignancy, with fewer than 40 % of patients surviving beyond five years. MiRNA-21 antisense oligonucleotides (anti-miR-21) hold considerable promise for managing aggressive intracranial gliomas. Yet, challenges such as in vivo degradation, suboptimal brain targeting, and inadequate tumor penetration compromise the therapeutic efficacy of unmodified miRNA-21 inhibitors. To overcome these obstacles, we designed an orally-administered, brain-targeted anti-miRNA-21 lipid polymer micelle system (BTMLPMS), dually modified with Ang-2 and TAT. This modification ensures the stable delivery of anti-miR-21, leveraging the protective capacities of lipid polymer micelles to effectively impede glioma growth in vivo. In vitro studies confirmed that these micelles were efficiently uptaken by glioma cells, resulting in induced apoptosis. Importantly, in an orthotopic glioma xenograft model using nude mice, oral administration of these micelles activated pro-apoptotic proteins p53 and Caspase-3, effectively inducing apoptosis in tumor tissues and curbing tumor progression. Hematoxylin-eosin staining further validated the biocompatibility of the micelles. Collectively, our findings underscore the potential of the anti-miR-21 lipid polymer micelle system as a significant advancement in glioma gene therapy, paving the way for groundbreaking transformations in miRNA clinical applications.