Tumor microenvironment immunomodulation by nanoformulated TLR 7/8 agonist and PI3k delta inhibitor enhances therapeutic benefits of radiotherapy.

Infiltration of immunosuppressive cells into the breast tumor microenvironment (TME) is associated with suppressed effector T cell (Teff) responses, accelerated tumor growth, and poor clinical outcomes. Previous studies from our group and others identified infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as critical contributors to immune dysfunction in the orthotopic claudin-low tumor model, limiting the efficacy of adoptive cellular therapy. However, approaches to target these cells in the TME are currently lacking. To overcome this barrier, polymeric micellular nanoparticles (PMNPs) were used for the co-delivery of small molecule drugs activating Toll-like receptors 7 and 8 (TLR7/8) and inhibiting PI3K delta (PI3Kδ). The immunomodulation of the TME by TLR7/8 agonist and PI3K inhibitor led to type 1 macrophage polarization, decreased MDSC accumulation and selectively decreased tissue-resident Tregs in the TME, while enhancing the T and B cell adaptive immune responses. PMNPs significantly enhanced the anti-tumor activity of local radiation therapy (RT) in mice bearing orthotopic claudin-low tumors compared to RT alone. Taken together, these data demonstrate that RT combined with a nanoformulated immunostimulant diminished the immunosuppressive TME resulting in tumor regression. These findings set the stage for clinical studies of this approach.

Red light-induced localized release of carbon monoxide for alleviating postoperative cognitive dysfunction.

Inflammation within the central nervous system (CNS), which may be triggered by surgical trauma, has been implicated as a significant factor contributing to postoperative cognitive dysfunction (POCD). The relationship between mitigating inflammation at peripheral surgical sites and its potential to attenuate the CNS inflammatory response, thereby easing POCD symptoms, remains uncertain. Notably, carbon monoxide (CO), a gasotransmitter, exhibits pronounced anti-inflammatory effects. Herein, we have developed carbon monoxide-releasing micelles (CORMs), a nanoparticle that safely and locally liberates CO upon exposure to 650 nm light irradiation. In a POCD mouse model, treatment with CORMs activated by light (CORMs + hv) markedly reduced the concentrations of interleukin (IL)-6, IL-1ß, and tumor necrosis factor-alpha (TNF-α) in both the peripheral blood and the hippocampus, alongside a decrease in ionized calcium-binding adapter molecule 1 in the hippocampal CA1 region. Furthermore, CORMs + hv treatment diminished Evans blue extravasation, augmented the expression of tight junction proteins zonula occludens-1 and occludin, enhanced neurocognitive functions, and fostered fracture healing. Bioinformatics analysis and experimental validation has identified Htr1b and Trhr as potential key regulators in the neuroactive ligand-receptor interaction signaling pathway implicated in POCD. This work offers new perspectives on the mechanisms driving POCD and avenues for therapeutic intervention.

A comparative study of PEO-PBO content on the targeting and anti-glioma activity of annonaceous acetogenins-loaded nanomicelles.

Annonaceous acetogenins (ACGs) have great potential in the treatment of gliomas, but are extremely insoluble and difficult for delivery in vivo. Poly(ethylene oxide)-b-poly(butylene oxide) (PEO-PBO) is an amphiphilic polymer and can reduce the clearance of nanoparticles by mononuclear phagocyte system. To explore an efficient and safe nanomedicine for glioma, ACGs-loaded nanomicelles (ACGs/EB-NCs) was constructed using PEO-PBO as a carrier, and the effect of PEO-PBO content on the targeting and anti-glioma activity were also compared. ACGs/EB5-NCs, ACGs/EB10-NCs and ACGs/EB20-NCs, the three nanomicellels prepared with different ACGs/EB feeding ratios, had average particle sizes of 148.8±0.5 nm, 32.7±4.1 nm, and 27.1±0.3 nm, respectively. The three ACGs/EB-NCs were spherical in shape, with drug loading content close to the theoretical drug loading content, encapsulation efficiency greater than 97 %, and good stability in physiological media. The cumulative release rates of ACGs/EB5-NCs, ACGs/EB10-NCs and ACGs/EB20-NCs were 78.2 %, 63.4 %, and 56.3 % within 216 hours, respectively. The inhibitory effects of three ACGs/EB-NCs on U87 MG cells were similar and stronger than free ACGs (P<0.05), with half inhibitory concentration of 0.17, 0.18, and 0.16 ng/mL (P>0.05), respectively. In U87 MG tumor­bearing mice, ACGs/EB5-NC, ACGs/EB10-NCs and ACGs/EB20-NCs showed a similar tumor inhibition rate of 61.1±5.9 %, 56.2±8.6 % and 64.3±9.4 % (P>0.05), with good safety. Three ACGs/EB-NCs exhibited excellent liver escape ability and tumor targeting ability, with the tumor targeting index greater than 1.5. Three ACGs/EB-NCs were successfully prepared with strong anti-glioma activity and tumor targeting properties, which are expected to provide new options for the clinical treatment of gliomas. The content of PEO-PBO in micelles did not have a significant effect on the tumor targeting and anti-glioma activity of ACGs/EB-NCs.

Hyaluronic Acid-Modified Micelles of Azithromycin and Quercetin Against Infections Caused by Methicillin-Resistant Staphylococcus Aureus.

Introduction: Resistance of intracellular pathogens is a challenge in microbial therapy. Methicillin-resistant Staphylococcus aureus (MRSA), which is able to persist inside the cells of infected tissues, is protected from attack by the immune system and many antimicrobial agents. To overcome these limitations, nano-delivery systems can be used for targeted therapy of intracellular MRSA. Methods: Hyaluronic acid-modified azithromycin/quercetin micelles (HA-AZI/Qe-M) were synthesized by thin film hydration. The micelles were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) and Fourier transform infrared spectroscopy (FTIR), and the drug loading (DL) and encapsulation efficiency (EE) were detected by high performance liquid chromatography (HPLC). The uptake ability of RAW264.7 cells was investigated, and its distribution in mice was evaluated by in vivo imaging. The inhibitory effect of the micelles against MRSA in vitro and its ability to eliminate intracellular bacteria were evaluated. Bacterial muscle-infected mice were constructed to evaluate the therapeutic effect of the micelles on bacterial infections in vivo and the biocompatibility of the micelles was investigated. Results: HA-AZI/Qe-M had suitable physical and chemical properties and characterization. In vitro antibacterial experiments showed that HA-AZI/Qe-M could effectively inhibit the growth of MRSA, inhibit and eliminate the biofilm formed by MRSA, and have an excellent therapeutic effect on intracellular bacterial infection. The results of RAW264.7 cells uptake and in vivo imaging showed that HA-AZI/Qe-M could increase the cellular uptake, target the infection site, and prolong the treatment time. The results of in vivo antibacterial infection experiments showed that HA-AZI/Qe-M was able to ameliorate the extent of thigh muscle infections in mice and reduce the expression of inflammatory factors. Conclusion: HA-AZI/Qe-M is a novel and effective nano-drug delivery system that can target intracellular bacterial infection, and it is expected to be safely used for the treatment of MRSA infection.

Hepatoma-Targeting and ROS-Responsive Polymeric Micelle-Based Chemotherapy Combined with Photodynamic Therapy for Hepatoma Treatment.

Background: The combination of nanoplatform-based chemotherapy and photodynamic therapy (PDT) is a promising way to treat cancer. Celastrol (Cela) exhibits highly effective anti-hepatoma activity with low water solubility, poor bioavailability, non-tumor targeting, and toxic side effects. The combination of Cela-based chemotherapy and PDT via hepatoma-targeting and reactive oxygen species (ROS)-responsive polymeric micelles (PMs) could solve the application problem of Cela and further enhance antitumor efficacy. Methods: In this study, Cela and photosensitizer chlorin e6 (Ce6) co-loaded glycyrrhetinic acid-modified carboxymethyl chitosan-thioketal-rhein (GCTR) PMs (Cela/Ce6/GCTR PMs) were prepared and characterized. The safety, ROS-sensitive drug release, and intracellular ROS production were evaluated. Furthermore, the in vitro anti-hepatoma effect and cellular uptaken in HepG2 and BEL-7402 cells, and in vivo pharmacokinetic, tissue distribution, and antitumor efficacy of Cela/Ce6/GCTR PMs in H22 tumor-bearing mice were then investigated. Results: Cela/Ce6/GCTR PMs were successfully prepared with nanometer-scale particle size, favorable drug loading capacity, and encapsulation efficiency. Cela/Ce6/GCTR PMs exhibited a strong safety profile and better hemocompatibility, exhibiting less damage to normal tissues. Compared with Cela-loaded GCTR PMs, the ROS-responsiveness of Cela/Ce6/GCTR PMs was increased, and the release of Cela was accelerated after combination with PDT. Cela/Ce6/GCTR PMs can efficiently target liver tumor cells by uptake and have a high cell-killing effect in response to ROS. The combination of GCTR PM-based chemotherapy and PDT resulted in increased bioavailability of Cela and Ce6, improved liver tumor targeting, and better anti-hepatoma effects in vivo. Conclusion: Hepatoma-targeting and ROS-responsive GCTR PMs co-loaded with Cela and Ce6 combined with PDT exhibited improved primary hepatic carcinoma therapeutic effects with lower toxicity to normal tissues, overcoming the limitations of monotherapy and providing new strategies for tumor treatment.

Secondary structure propensities of the Ebola delta peptide E40 in solution and model membrane environments.

The Ebola delta peptide is an amphipathic, 40-residue peptide encoded by the Ebola virus, referred to as E40. The membrane-permeabilising activity of the E40 delta peptide has been demonstrated in cells and lipid vesicles suggesting the E40 delta peptide likely acts as a viroporin. The lytic activity of the peptide increases in the presence of anionic lipids and a disulphide bond in the C-terminal part of the peptide. Previous in silico work predicts the peptide to show a partially helical structure, but there is no experimental information on the structure of E40. Here, we use circular dichroism spectroscopy to report the secondary structure propensities of the reduced and oxidised forms of the E40 peptide in water, detergent micelles, and lipid vesicles composed of neutral and anionic lipids (POPC and POPG, respectively). Results indicate that the peptide is predominately a random coil in solution, and the disulphide bond has a small but measurable effect on peptide conformation. Secondary structure analysis shows large uncertainties and dependence on the reference data set and, in our system, cannot be used to accurately determine the secondary structure motifs of the peptide in membrane environments. Nevertheless, the spectra can be used to assess the relative changes in secondary structure propensities of the peptide depending on the solvent environment and disulphide bond. In POPC-POPG vesicles, the peptide transitions from a random coil towards a more structured conformation, which is even more pronounced in negatively charged SDS micelles. In vesicles, the effect depends on the peptide-lipid ratio, likely resulting from vesicle surface saturation. Further experiments with zwitterionic POPC vesicles and DPC micelles show that both curvature and negatively charged lipids can induce a change in conformation, with the two effects being cumulative. Electrostatic screening from Na+ ions reduced this effect. The oxidised form of the peptide shows a slightly lower propensity for secondary structure and retains a more random coil conformation even in the presence of PG-PC vesicles.

Influence of Redox-Active Chitosan-Polyaminoxyl Micelles Loaded with Daunorubicin on Activity of Nrf2 Transcription Factor.

A new system for delivery of anthracycline antibiotics based on chitosan-polyaminoxyls (CPA) was studied in a model of non-tumor (human embryonic mesenchymal stem cells) and tumor cells (human hepatocellular carcinoma) in vitro. The presence of CPA micelles considerably suppresses daunorubicin-induced ROS generation in normal cells without affecting this process in tumor cells. CPA micelles do not reduce the cytotoxic effect of daunorubicin and do not prevent its accumulation in cells. The use of CPA significantly increases accumulation of Nrf2 transcription factor in the nuclei of both normal and tumor cells in comparison with free daunorubicin. Increased nuclear translocation of Nrf2 leads to a significant increase in the expression of its target gene TXN1, but not the NQO1, GPX1, and HMOX1 genes, the increased expression of which can lead to the development of resistance to anthracycline antibiotics. Redox-active CPA micelles have great potential for the development of nanoparticles for the transport of anthracycline antibiotics in experimental tumor chemotherapy, and also as promising activators of Nrf2 transcription factor.

ROS-triggered and macrophage-targeted micelles modulate mitochondria function and polarization in obesity.

Inflammation involving adipose macrophages is an important inducer of obesity. Regulating macrophages polarization and improving the inflammatory microenvironment of adipose tissue is a new strategy for the treatment of obesity. An amphiphilic chondroitin sulfate phenylborate derivative (CS-PBE) was obtained by modifying the main chain of chondroitin sulfate with the hydrophobic small molecule phenylborate. Using CS-PBE self-assembly, macrophage targeting, reactive oxygen species (ROS) release and celastrol (CLT) encapsulation were achieved. The cytotoxicity, cellular uptake, internalization pathways and transmembrane transport efficiency of CS-PBE micelles were studied in Caco-2 and RAW264.7 cells. Hemolysis and organotoxicity tests were performed to assess the safety of the platform, while its therapeutic efficacy was investigated in high-fat diet-induced obese mice. Multifunctional micelles with macrophage targeting and ROS clearance capabilities were developed to improve the efficacy of CLT in treating obesity.In vitrostudies indicated that CS-PBE micelles had better ability to target M1 macrophages, better protective effects on mitochondrial function, better ability to reduce the number of LPS-stimulated M1 macrophages, better ability to reduce the number of M2 macrophages, and better ability to scavenge ROS in inflammatory macrophages.In vivostudies have shown that CS-PBE micelles improve inflammation and significantly reduce toxicity of CLT in the treatment of obesity. In summary, CS-PBE micelles could significantly improve the ability to target inflammatory macrophages and scavenge ROS in adipose tissue to alleviate inflammation, suggesting that CS-PBE micelles are a highly promising approach for the treatment of obesity.

Renal-Targeted Drug Delivery by Chitosan Oligosaccharide Micelles with HSA-Enriched Protein Corona for the Treatment of Ischemia/Reperfusion-Induced Acute Kidney Injury.

Renal-specific nanoparticulate drug delivery systems have shown great potential in reducing systemic side effects and improving the safety and efficacy of treatments for renal diseases. Here, stearic acid-grafted chitosan oligosaccharide (COS-SA) was synthesized as a renal-targeted carrier due to the high affinity of the 2-glucosamine moiety on COS to the megalin receptor expressed on renal proximal tubular epithelial cells. Specifically, COS-SA/CLT micelles were prepared by encapsulating celastrol (CLT) with COS-SA, and different proportions of human serum albumin (HSA) were then adsorbed onto its surface to explore the interaction between the protein corona and cationic polymeric micelles. Our results showed that a multilayered protein corona, consisting of an inner "hard" corona and an outer "soft" corona, was formed on the surface of COS-SA/CLT@HSA8, which was beneficial in preventing its recognition and phagocytosis by macrophages. The formation of HSA protein corona on COS-SA/CLT micelles also increased its accumulation in the renal tubules. Furthermore, the electropositivity of COS-SA/CLT micelles affected the conformation of adsorbed proteins to various degrees. During the adsorption process, the protein corona on the surface of COS-SA/CLT@HSA1 was partially denatured. Overall, COS-SA/CLT and COS-SA/CLT@HSA micelles demonstrated sufficient safety with renal targeting potential, providing a viable strategy for the management of ischemia/reperfusion-induced acute kidney injury.

Superresolution imaging of antibiotic-induced structural disruption of bacteria enabled by photochromic glycomicelles.

Bacterial evolution, particularly in hospital settings, is leading to an increase in multidrug resistance. Understanding the basis for this resistance is critical as it can drive discovery of new antibiotics while allowing the clinical use of known antibiotics to be optimized. Here, we report a photoactive chemical probe for superresolution microscopy that allows for the in situ probing of antibiotic-induced structural disruption of bacteria. Conjugation between a spiropyran (SP) and galactose via click chemistry produces an amphiphilic photochromic glycoprobe, which self-assembles into glycomicelles in water. The hydrophobic inner core of the glycomicelles allows encapsulation of antibiotics. Photoirradiation then serves to convert the SP to the corresponding merocyanine (MR) form. This results in micellar disassembly allowing for release of the antibiotic in an on-demand fashion. The glycomicelles of this study adhere selectively to the surface of a Gram-negative bacterium through multivalent sugar-lectin interaction. Antibiotic release from the glycomicelles then induces membrane collapse. This dynamic process can be imaged in situ by superresolution spectroscopy owing to the "fluorescence blinking" of the SP/MR photochromic pair. This research provides a high-precision imaging tool that may be used to visualize how antibiotics disrupt the structural integrity of bacteria in real time.

Preparation of transferrin-targeted temozolomide nano-micelles and their anti-glioma effect.

Objectives: This study aims to develop brain-targeted temozolomide (TMZ) nanograins using the biodegradable polymer material PEG-PLA as a carrier. The model drug TMZ was encapsulated within the polymer using targeted nanotechnology. Key characteristics such as appearance, particle size, size distribution, drug loading capacity, in vitro release rate, stability, and anti-tumor effects were systematically evaluated through in vitro experiments. Methods: Transmission electron microscopy (TEM) and Malvern size analyzer were employed to observe the morphological and particle size features of the TMZ nanospheres at various time points to assess stability. The effects of TMZ nanograins on glioma cell viability and apoptosis were evaluated using MTT assays and flow cytometry. Results: The targeted TMZ nano-micelles were successfully synthesized. After loading and targeted modifications, the particle size increased from 50.7 to 190 nm, indicating successful encapsulation of TMZ. The average particle size of the nano-micelles remained stable around 145 ± 10 nm at 1 day, 15 days, and 30 days post-preparation. The release rate of the nano-micelles was monitored at 2 h, 12 h, 24 h, and 48 h post-dialysis, ultimately reaching 95.8%. Compared to TMZ alone, the TMZ-loaded PEG-PLA nano-micelles exhibited enhanced cytotoxicity and apoptosis in glioma cells. This was accompanied by increased mitochondrial membrane potential and reactive oxygen species (ROS) levels following treatment with the TMZ nano-micelles. Conclusions: TMZ-loaded nano-micelles demonstrated a gradual release profile and significantly enhanced inhibitory effects on human glioma U251 cells compared to TMZ alone. The findings suggest that TMZ-loaded PEG-PLA nano-micelles may offer a more effective therapeutic approach for glioma treatment.

Development and Optimization of a Bromothymol Blue-Based PLA2 Assay Involving POPC-Based Self-Assemblies.

Phospholipase A2 (PLA2) is a superfamily of phospholipase enzymes that dock at the water/oil interface of phospholipid assemblies, hydrolyzing the ester bond at the sn-2 position. The enzymatic activity of these enzymes differs based on the nature of the substrate, its supramolecular assemblies (micelle, liposomes), and their composition, reflecting the interfacial nature of the PLA2s and requiring assays able to directly quantify this interaction of the enzyme(s) with these supramolecular assemblies. We developed and optimized a simple, universal assay method employing the pH-sensitive indicator dye bromothymol blue (BTB), in which different POPC (3-palmitoyl-2-oleoyl-sn-glycero-1-phosphocholine) self-assemblies (liposomes or mixed micelles with Triton X-100 at different molar ratios) were used to assess the enzymatic activity. We used this assay to perform a comparative analysis of PLA2 kinetics on these supramolecular assemblies and to determine the kinetic parameters of PLA2 isozymes IB and IIA for each supramolecular POPC assembly. This assay is suitable for assessing the inhibition of PLA2s with great accuracy using UV-VIS spectrophotometry, being thus amenable for screening of PLA2 enzymes and their substrates and inhibitors in conditions very similar to physiologic ones.

Impact of a poly(ethylene glycol) corona block on drug encapsulation during polymerization induced self-assembly.

Polymerization induced self-assembly (PISA) provides a facile platform for encapsulating therapeutics within block copolymer nanoparticles. Performing PISA in the presence of a hydrophobic drug alters both the nanoparticle shape and encapsulation efficiency. While previous studies primarily examined the interactions between the drug and hydrophobic core block, this work explores the impact of the hydrophilic corona block on encapsulation. Poly(ethylene glycol) (PEG) and poly(2-hydroxypropyl methacrylate) (PHPMA) are used as the model corona and core blocks, respectively, and phenylacetic acid (PA) is employed as the model drug. Attachment of a dithiobenzoate end group to the PEG homopolymer - transforming it into a macroscopic reversible addition-fragmentation chain transfer agent - causes the polymer to form a small number of nanoscopic aggregates in solution. Adding PA to the PEG solution encourages further aggregation and macroscopic phase separation. During the PISA of PEG-PHPMA block copolymers, inclusion of PA in the reaction mixture promotes faster nucleation of spherical micelles. Although increasing the targeted PA loading from 0 to 20 mg mL-1 does not affect the micelle size or shape, it alters the drug spatial distribution within the PISA microenvironment. PA partitions into either PEG-PHPMA micelles, deuterium oxide, or other polymeric species - including PEG aggregates and unimer chains. Increasing the targeted PA loading changes the fraction of drug within each encapsulation site. This work indicates that the corona block plays a critical role in dictating drug encapsulation during PISA.

Mucosal Penetrative Polymeric Micelle Formulations for Insulin Delivery to the Respiratory Tract.

Purpose: Effective mucosal delivery of drugs continues to pose a significant challenge owing to the formidable barrier presented by the respiratory tract mucus, which efficiently traps and clears foreign particulates. The surface characteristics of micelles dictate their ability to penetrate the respiratory tract mucus. In this study, polymeric micelles loaded with insulin (INS) were modified using mucus-penetrative polymers. Methods: We prepared and compared polyethylene glycol (PEG)-coated micelles with micelles where cell-penetrating peptide (CPP) is conjugated to PEG. Systematic investigations of the physicochemical and aerosolization properties, performance, in vitro release, mucus and cell penetration, lung function, and pharmacokinetics/pharmacodynamics (PK/PD) of polymeric micelles were performed to evaluate their interaction with the respiratory tract. Results: The nano-micelles, with a particle size of <100 nm, exhibited a sustained-release profile. Interestingly, PEG-coated micelles exhibited higher diffusion and deeper penetration across the mucus layer. In addition, CPP-modified micelles showed enhanced in vitro cell penetration. Finally, in the PK/PD studies, the micellar solution demonstrated higher maximum concentration (Cmax) and AUC0-8h values than subcutaneously administered INS solution, along with a sustained blood glucose-lowering effect that lasted for more than 8 h. Conclusion: This study proposes the use of mucus-penetrating micelle formulations as prospective inhalation nano-carriers capable of efficiently transporting peptides to the respiratory tract.

GSH-responsive polymeric micelles-based augmented photoimmunotherapy synergized with PD-1 blockade for eliciting robust antitumor immunity against colon tumor.

Phototherapy is a promising antitumor modality, which consists of photothermal therapy (PTT) and photodynamic therapy (PDT). However, the efficacy of phototherapy is dramatically hampered by local hypoxia in tumors, overexpression of indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand-1 (PD-L1) on tumor cells. To address these issues, self-assembled multifunctional polymeric micelles (RIMNA) were developed to co-deliver photosensitizer indocyanine green (ICG), oxygenator MnO2, IDO inhibitor NLG919, and toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). It is worth noting that RIMNA polymeric micelles had good stability, uniform morphology, superior biocompatibility, and intensified PTT/PDT effect. What's more, RIMNA-mediated IDO inhibition combined with programmed death receptor-1 (PD-1)/PD-L1 blockade considerably improved immunosuppression and promoted immune activation. RIMNA-based photoimmunotherapy synergized with PD-1 antibody could remarkably inhibit primary tumor proliferation, as well as stimulate the immunity to greatly suppress lung metastasis and distant tumor growth. This study offers an efficient method to reinforce the efficacy of phototherapy and alleviate immunosuppression, thereby bringing clinical benefits to cancer treatment.

Micellar delivery systems of bioactive compounds for precision nutrition.

Rapid changes in lifestyle and the increasingly hectic pace of life have led to a rise in chronic diseases, such as obesity, inflammatory bowel disease, liver disease, and cancer, posing significant threats to public health. In response to these challenges, precision nutrition (PN) has emerged as a secure and effective intervention aiming at human health and well-being. Bioactive compounds (bioactives), including carotenoids, polyphenols, vitamins, and polyunsaturated fatty acids, exhibit a range of beneficial properties, e.g., antioxidant and anti-inflammatory effects. These properties make them promising candidates for preventing or treating chronic diseases and promoting human health. However, bioactives might have different challenges when incorporated into food matrices and oral administration, including low water solubility, poor physiochemical stability, and low absorption efficiency. This limits them to achieve the health benefits in the body. Numerous strategies have been developed and utilized to encapsulate and deliver bioactives. Micellar delivery systems, due to their unique core-shell structure, play a pivotal role in improving the stability, solubility, and bioavailability of these bioactives. Moreover, through innovative design strategies, micellar delivery systems can be tailored to offer targeted and controlled release, thus maximizing the potential of bioactives in PN applications. This chapter reveals details about the preparation methods and properties of micelles and highlights the strategies to modulate the properties of polymeric micelles. Afterwards, the application of polymeric micelles in the delivery of bioactives and the corresponding PN, including controlled release, organ-targeting ability, and nutritional intervention for chronic disease are summarized.

Reactive oxygen species sensitive nanomicelles promote the antifungal activity of ketoconazole against Candida albicans in vulvovaginal candidiasis.

Excessive local accumulation of reactive oxygen species (ROS) in vulvovaginal candidiasis (VVC) leads to oxidative stress and aggravates inflammation. This study aimed to optimize and synthesize four ROS-sensitive polyethylene glycol (PEG)-boride polymers (PB, PCB, BPB, and BCPCB). A nanomicelle (BCPCB-K) was constructed using BCPCB-encapsulated ketoconazole (KTZ). Finally, the depolymerization principle and ROS-sensitive drug release of BCPCB-K as well as its anti-Candida albicans (CA) and therapeutic effects on mice with VVC were explored through in vitro and in vivo experiments. BCPCB-K exhibited low toxicity to mammalian cells in vitro and good biocompatibility in vivo. It also improved the dispersion and solubility of the hydrophobic drug KTZ. Furthermore, BCPCB-K simultaneously scavenged ROS and released the drug, thus facilitating the antifungal and VVC-treating effects of KTZ. Overall, the findings of this study broadened the application of ROS-sensitive materials in the drug-loading and antifungal fields and provided a strategy for VVC treatment.

Anticancer drug delivery: Investigating the impacts of viscosity on lipid-based formulations for pulmonary targeting.

Pulmonary drug delivery via aerosolization is a non-intrusive method for achieving localized and systemic effects. The aim of this study was to establish the impact of viscosity as a novel aspect (i.e., low, medium and high) using various lipid-based formulations (including liposomes (F1-F3), transfersomes (F4-F6), micelles (F7-F9) and nanostructured lipid carriers (NLCs; F10-F12)) as well as to investigate their impact on in-vitro nebulization performance using Trans-resveratrol (TRES) as a model anticancer drug. Based on the physicochemical properties, micelles (F7-F9) elicited the smallest particle size (12-174 nm); additionally, all formulations tested exhibited high entrapment efficiency (>89 %). Through measurement using capillary viscometers, NLC formulations exhibited the highest viscosity (3.35-10.04 m2/sec). Upon using a rotational rheometer, formulations exhibited shear-thinning (non-Newtonian) behaviour. Air jet and vibrating mesh nebulizers were subsequently employed to assess nebulization performance using an in-vitro model. Higher viscosity formulations elicited a prolonged nebulization time. The vibrating mesh nebulizer exhibited significantly higher emitted dose (ED), fine particle fraction (FPF) and fine particle dose (FPD) (up to 97 %, 90 % and 64 µg). Moreover, the in-vitro release of TRES was higher at pH 5, demonstrating an alignment of the release profile with the Korsmeyer-Peppas model. Thus, formulations with higher viscosity paired with a vibrating mesh nebulizer were an ideal combination for delivering and targeting peripheral lungs.

Intelligent micelles for on-demand drug delivery targeting extracellular matrix of pancreatic cancer.

As a key pathological feature of pancreatic ductal adenocarcinoma(PDAC), the dense extracellular matrix(ECM) limits the penetration of chemotherapy drugs and is involved in the formation of immunosuppressive microenvironment. Meanwhile, clinical practice has shown that the treatment strategy for ECM should consider its restriction of tumor cell metastasis, and the need for in-depth chemotherapy without destroying ECM is proposed. STAT3 inhibitors have been reported to regulate tumor microenvironment including interrupt the form of ECM. Therefore, we designed and established a micelle system MP@HA with in vivo targeting and responsive drug release function co-loading gemcitabine monophosphate and STAT3 inhibitor silibinin. The hyaluronic acid on the surface of the micelle can bind specifically to the CD44 molecule on the surface of tumor cells and help micelles accumulate at the tumor site. The nitroimidazole used to modify the polymeric skeleton can make the micellar structure collapse in response to hypoxia reduction conditions in the tumor environment, and release silibinin to widely regulate STAT3 molecules in the PDAC microenvironment. The polymer fragment attached with gemcitabine monophosphate can penetrate deep into PDAC tumors due to its small size and positive charge exposed, achieving deep chemotherapy. This research indicates a promising micelle system meeting complicated demands proposed in PDAC treatment to improve antitumor efficacy.

Inhalable mucin-permeable nanomicelles deliver antibiotics for effective treatment of chronic pneumonia.

Pseudomonas aeruginosa (P. aeruginosa) pneumonia can have serious physiological consequences, particularly when P. aeruginosa biofilms are formed. Although inhaled therapy is preferred, inhaled drugs tend to get trapped by pulmonary mucus, which hinders efficient antibiotic permeability through mucus and biofilms. In this study, we prepare poly[2-(pentamethyleneimino)ethyl methacrylate]-block-poly[2-(N-oxide-pentamethyleneimino)ethyl methacrylate] (PPEMA-b-PPOEMA) micelles loaded with azithromycin (AZM) using reversible addition-fragmentation chain transfer (RAFT) polymerization to achieve effective treatment of P. aeruginosa pneumonia. The zwitterionic structure on the surface of the micelle facilitates the successful traversal of the mucus and optimal concentration within the biofilm. Furthermore, the protonation of piperidine in the polymer enables the micelles to exhibit a positive charge in the acidic environment of a bacterial infection, enhancing AZM's interaction with the bacterium. Both in vivo and in vitro experiments demonstrate that this transmucosal zwitterionic polymer, in combination with a charge reversal strategy, effectively promotes the enrichment of micelles at the site of bacterial infection, thereby increasing the number of antibiotics reaching the bacterial interior and demonstrating remarkable antibacterial synergy. Overall, this work offers a promising approach for trans-airway drug delivery in the treatment of pneumonia.