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Simple Summary: Many studies have evaluated the spread and transmission of SARS-CoV-2 and MERS-CoV in humans; however, the ability of the virus to infect pets, including dogs, has not been fully clarified. Accordingly, in this study, we evaluated the ability of SARS-CoV-2 and MERS-CoV to infect beagle dogs. Our results showed that dogs can be infected by both viruses. Viral shedding into nasal secretions, feces, and urine was observed, and the lung tissues from the dogs inoculated with SARS-CoV-2 or MERS-CoV showed pathological changes, as well as changes in their lactate dehydrogenase levels. The coronavirus disease 19 (COVID-19) pandemic, caused by the severe acute respiratory syndrome, coronavirus 2 (SARS-CoV-2), has resulted in unprecedented challenges to healthcare worldwide. In particular, the anthroponotic transmission of human coronaviruses has become a common concern among pet owners. Here, we experimentally inoculated beagle dogs with SARS-CoV-2 or Middle East respiratory syndrome (MERS-CoV) to compare their susceptibility to and the pathogenicity of these viruses. The dogs in this study exhibited weight loss and increased body temperatures and shed the viruses in their nasal secretions, feces, and urine. Pathologic changes were observed in the lungs of the dogs inoculated with SARS-CoV-2 or MERS-CoV. Additionally, clinical characteristics of SARS-CoV-2, such as increased lactate dehydrogenase levels, were identified in the current study. [ABSTRACT FROM AUTHOR]

This paper presents a novel convolutional layer, called perturbed convolution (PConv), which performs not only a convolution operation but also a dropout one. The PConv focuses on achieving two goals simultaneously: improving the generative adversarial network (GAN) performance and alleviating the memorization problem in which the discriminator memorizes all images from a given dataset as training progresses. In PConv, perturbed features are generated by randomly disturbing an input tensor before performing the convolution operation. This approach is simple but surprisingly effective. First, to produce a similar output even with the perturbed tensor, each layer in the discriminator should learn robust features having a small local Lipschitz value. Second, since the input tensor is randomly perturbed during the training procedure like the dropout in neural networks, the memorization problem could be alleviated. To show the generalization ability of the proposed method, we conducted extensive experiments with various loss functions and datasets including CIFAR-10, CelebA, CelebA-HQ, LSUN, and tiny-ImageNet. The quantitative evaluations demonstrate that PConv effectively boosts the performance of GAN and conditional GAN in terms of Frechet inception distance (FID). [ABSTRACT FROM AUTHOR]

Macrophages are prevalent in the body and have roles in almost every aspect of human biology. They have often been considered a subject to avoid during drug delivery. However, with recent understanding of their diverse functions in diseases, macrophages have gained increasing interest as important therapeutic targets. To develop drug carriers to macrophages, it is important to understand their biological roles and requirements for efficient targeting. This review provides an overview of representative carriers and various approaches to address challenges in drug delivery to macrophages such as biodistribution, cellular uptake, intracellular trafficking, and drug release. [ABSTRACT FROM AUTHOR]

Nanocarriers providing spatiotemporal control of drug release contribute to reducing toxicity and improving therapeutic efficacy of a drug. On the other hand, nanocarriers face unique challenges in controlling drug release kinetics, due to the large surface area per volume ratio and the short diffusion distance. To develop nanocarriers with desirable release kinetics for target applications, it is important to understand the mechanisms by which a carrier retains and releases a drug, the effects of composition and morphology of the carrier on the drug release kinetics, and current techniques for preparation and modification of nanocarriers. This review provides an overview of drug release mechanisms and various nanocarriers with a specific emphasis on approaches to control the drug release kinetics. [ABSTRACT FROM AUTHOR]

Abstract: Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) conjugated to a cell-penetrating peptide, TAT, was used to increase intracellular delivery of paclitaxel (PTX) to multi-drug resistant (MDR) cells. Efficient cellular uptake of the TAT-conjugated PLGA NPs was observed; however, it did not translate to increased killing of MDR cells. An investigation of drug release kinetics in phosphate-buffered saline containing Tween 80 led us to suspect that a significant fraction of the loaded PTX was released before efficient cellular uptake could occur. These results indicate that the increased cellular uptake of NPs does not always mean an enhanced drug effect and that it is critical to control both the location of NPs and the drug release from NPs together. Based on this study, we propose that two prevalent practices in NP research be reconsidered: first, the utility of a new NP system should be tested beyond the imaging level. Second, NP release kinetics should be monitored in a medium that can reflect the complexity of biological environment rather than a simple buffered saline. [Copyright &y& Elsevier]

Abstract: Nanocrystals have drawn increasing interest in pharmaceutical industry because of the ability to improve dissolution of poorly water-soluble drugs. Nanocrystals can be produced by top-down and bottom-up technologies and have been explored for a variety of therapeutic applications. Here we review the methods of nanocrystal production and parenteral applications of nanocrystals. We also discuss remaining challenges in the development of nanocrystal products. [Copyright &y& Elsevier]

Stiff extracellular matrix, elevated interstitial fluid pressure, and the affinity for the tumor cells in the peripheral region of a solid tumor mass have long been recognized as significant barriers to diffusion of small-molecular-weight drugs and antibodies. However, their impacts on nanoparticle-based drug delivery have begun to receive due attention only recently. This article reviews biological features of many solid tumors that influence transport of drugs and nanoparticles and properties of nanoparticles relevant to their intratumoral transport, studied in various tumor models. We also discuss several experimental approaches employed to date for enhancement of intratumoral nanoparticle penetration. The impact of nanoparticle distribution on the effectiveness of chemotherapy remains to be investigated and should be considered in the design of new nanoparticulate drug carriers. [ABSTRACT FROM AUTHOR]

Abstract: Peritoneal adhesions are serious complications of surgery, and can result in pain, infertility, and potentially lethal bowel obstruction. Pharmacotherapy and barrier devices have reduced adhesion formation to varying degrees in preclinical studies or clinical trials; however, complete prevention of adhesions remains to be accomplished. We and others have hypothesized that the limitations of the two approaches could be overcome by combining their strengths in the context of controlled drug delivery. Here we review the role of polymeric systems in the prevention of peritoneal adhesions, with an emphasis on our recent work in developing and applying polymeric drug delivery systems such as nano- or microparticles, hydrogels, and hybrid systems for peritoneal use. [Copyright &y& Elsevier]

Abstract: Postoperative peritoneal adhesions can have serious, potentially lethal consequences. Pharmacotherapy and barrier devices can reduce adhesion formation to varying degrees, but their efficacy is limited by rapid clearance from the peritoneum and lack of biological activity, respectively. To overcome these limitations, we have delivered tissue-type plasminogen activator (tPA), which is deficient in the first 2–3 postoperative days, using a highly cross-linked in situ forming hyaluronan gel (HAXhx). We demonstrated this formulation''s anti-adhesion activity in a rigorous animal model that involved recurrent adhesions. While non-treated or saline-treated animals developed widespread adhesions (frequency, both 100%; median adhesion area, 12.7 and 15.4cm2, respectively), tPA delivered by HAXhx (tPA-HAXhx) was highly effective in preventing recurrent adhesions (frequency, 44%; median adhesion area, 0.1cm2). HAXhx itself, tPA solution, and inactivated tPA in HAXhx did not provide comparable anti-adhesion activity. tPA-HAXhx is a system that is easy to use and potentially promising for adhesion prevention. [Copyright &y& Elsevier]

Abstract: Peritoneal adhesions are serious sequelae of surgery, and can cause significant morbidity and/or mortality due to pain, infertility, and bowel obstruction. We have designed and synthesized novel dextran (DX)-based injectable hydrogels for adhesion prevention, which are formed by mixing hydrazide-modified carboxymethyldextran (CMDX–ADH) with aldehyde-modified DX (DX–CHO) or carboxymethylcellulose (CMC–CHO). At high polymer concentrations, hydrogels formed very quickly upon mixing, e.g. 5% CMDX–ADH with 6% DX–CHO (13;DX; 1.8s) and 5% CMDX–ADH with 6% CMC–CHO (13;CMC; 5.8s). CMDX–DX shrank after gelling, while CMDX–CMC swelled. CMDX–ADH and CMC–CHO showed minimal to mild cytotoxicity to mesothelial cells and macrophages in vitro, while DX–CHO was very cytotoxic. However, all cross-linked gels had very mild cytotoxicity. When applied in a rabbit sidewall defect-bowel abrasion model of adhesion formation, CMDX–CMC greatly reduced the formation of adhesions while CMDX–DX worsened them. [Copyright &y& Elsevier]

Abstract: Peritoneal adhesions are tissue connections that form within the abdominopelvic cavity following surgery or other injuries. They can cause major medical complications. Barrier devices and pharmacological agents have been used to prevent adhesion formation, with mixed success. We hypothesize that an adhesion barrier which also delivers anti-adhesion drugs can address both physical and physiological causes for adhesion formation. Here, we describe an in situ cross-linking hyaluronan hydrogel (barrier device) containing the glucocorticoid receptor agonist budesonide. Budesonide was chosen because of the known role of inflammation in adhesion formation, hyaluronan because of its known biocompatibility in the peritoneum. The system, consisting of two cross-linkable precursor liquids, was applied using a double-barreled syringe, forming a flexible and durable hydrogel in less than 5 s. We applied this formulation or controls to the injured sites after the second injury in a severe repeat sidewall defect–cecum abrasion model of peritoneal adhesion formation in the rabbit. Large adhesions (median area 15.4 cm2) developed in all saline-treated animals. Adhesion formation and area were slightly mitigated in animals treated with budesonide in saline (median area 5.0 cm2) or the hydrogel without budesonide (median area 4.9 cm2). The incidence and area of adhesions were dramatically reduced in animals treated with budesonide in the hydrogel (median area 0.0 cm2). In subcutaneous injections in rats, budesonide in hydrogel reduced inflammation compared to hydrogel alone. In summary, budesonide in a hyaluronan hydrogel is easy to use and highly effective in preventing adhesions in our severe repeated injury model. It is a potentially promising system for post-surgical adhesion prevention, and suggests that the effectiveness of barrier devices can be greatly enhanced by concurrent drug delivery. [Copyright &y& Elsevier]

Abstract: Post-operative peritoneal adhesions can cause pelvic pain, infertility, and potentially lethal bowel obstruction. We have designed and synthesized injectable hydrogels that are formed by mixing hydrazide-modified hyaluronic acid (HA) with aldehyde-modified versions of cellulose derivatives such as carboxymethylcellulose (CMC), hydroxypropylmethylcellulose (HPMC), and methylcellulose (MC). Gelation of these hydrogels occurred in less than 1min, and had higher shear moduli than that of HA–HA gel (HAX). Hydrogels degraded in the presence of hyaluronidase in vitro, with HA–MC and HA–HPMC degrading more slowly than HAX and HA–CMC. The aldehyde-modified cellulose derivatives showed dose-dependent mild-to-moderate cytotoxicity to mesothelial cells and macrophages in vitro, but all were biocompatible in the murine peritoneum, causing no adhesions for 3 weeks. All the cellulose-derived gels showed efficacy in reducing the area of adhesion formation in a rabbit sidewall defect-bowel abrasion model. [Copyright &y& Elsevier]

Abstract: Here we describe a simple and rapid system for creation of patterned cell culture substrates. This technique is based on (1) printing a mask on a standard overhead transparency, (2) coating a thin layer of a photocrosslinkable chitosan on a slide, (3) exposing the slide and mask to ultraviolet (UV) light, and (4) rinsing the uncrosslinked polymer to expose the underlying cell-repellent patterns. Photocross-linkable chitosan does not require photoinitiators, it is non-toxic and forms flexible, biocompatible hydrogel upon short (∼min) UV exposure. Patterns of various shapes (lanes, squares, triangles, circles) were created on two surfaces commonly used for cell culture: glass and tissue culture polystyrene. The pattern size could be varied with a μm resolution using a single mask and varying UV exposure time. Cardiac fibroblasts formed stable patterns for up to 18 days in culture. Cardiomyocytes, patterned in lanes 68–99μm wide, exhibited expression of cardiac Troponin I, well developed contractile apparatus and they contracted synchronously in response to electrical field stimulation. Osteoblasts (SAOS-2) localized in the exposed glass regions (squares, triangles, or circles; 0.063–0.5mm2). They proliferated to confluence in 5 days, expressed alkaline phosphatase and produced a mineralized matrix. [Copyright &y& Elsevier]

Abstract: We studied the efficacy of an in situ cross-linked hyaluronic acid hydrogel (HAX) in preventing post-surgical peritoneal adhesions, using a rabbit sidewall defect-cecum abrasion model. Two cross-linkable precursors were prepared by modifying hyaluronic acid with adipic dihydrazide and aldehyde, respectively. The hydrogel precursors cross-linked to form a flexible hydrogel upon mixing. The hydrogel was biodegradable and provided a durable physical barrier, which was highly effective in reducing the formation of post-operative adhesions. Ten out of 12 animals in the untreated control group developed fibrous adhesions requiring sharp dissection, while only 2 out of 8 animals treated with HAX gels showed such adhesions, and those occurred in locations that were not covered by the hydrogel. We also studied means by which gel degradation time can be modulated by varying the precursor concentration and molecular weight. [Copyright &y& Elsevier]

Abstract: Reservoir-type microcapsules were produced in a mild and highly efficient manner using a coaxial ultrasonic atomizer. To understand the microencapsulation mechanism, the atomizer was operated in different modes. The results suggested the reservoir-type microcapsules were formed by midair collision of the microdrops of the two component liquids consisting of a polymer solution and an aqueous solution. The encapsulation efficiency and the distribution of the microdrops captured in midair were dependent on the ratio of the flow rates of the two liquids, which suggested that the collision involved multiple microdrops. This method allowed lysozyme to be encapsulated without loss of functional integrity and to be released with near zero-order kinetics for over 50 days. The ultrasonic atomizer provided a new method of preparing reservoir-type microcapsules. [Copyright &y& Elsevier]

A new microencapsulation technique that utilizes interfacial mass transfer between two mutually soluble liquids has been developed. The technique is based on formation of a solid polymer film at the interface of a solution of a water-insoluble polymer and an aqueous solution, resulting from the mutual mass transfer of solvents (i.e., solvent exchange). Reservoir-type microcapsules were prepared by inducing this phenomenon to occur on the surface of an aqueous droplet. One method of implementation employed a dual microdispenser system that consisted of two ink-jet nozzles. The nozzles, producing droplets of a polymer solution and an aqueous drug solution, respectively, were aligned to allow collision of pairs of the droplets. The collision resulted in spreading of the polymer solution on the aqueous droplet and simultaneous solvent exchange, to form a polymeric membrane around the aqueous droplet. The formation of the polymer membrane depended largely on the favorable spreading of the polymer solution on the aqueous droplets and fast solvent exchange, and required judicious selection of the organic solvent. Simple and fast screening methods were developed for selection of a proper solvent. Ethyl acetate was chosen as one of the most desirable solvents through the screening procedures. Ethyl acetate and the dual microdispenser system were used to form microcapsules that were subsequently examined by microscopic methods to demonstrate their unique geometry. [Copyright &y& Elsevier]

High-density coherent fiber bundles, mainly used for high-resolution fiberscopes, consist of non-circular cores and have various optical noises such as auto-fluorescence, crosstalk, and honeycomb artifacts that may require excessive image processing. Binarization was applied to post-image processing to eliminate a calibration used as pre-image processing for traditional fiberscope image reconstruction. It was able to significantly reduce the complexity of implementing core peak detection and effectively reduce the overall processing time. For binarization, the global thresholding suggested by Otsu and the local thresholdings suggested by Bernsen, Niblack, and White and Rohrer were used. By applying a dynamic method to our method, we can further simplify the process and apply it to image sequencing. When evaluating the results comprehensively, the local thresholding proposed by Bernsen was best suited for interpolating our fiberscope images. By introducing binarization combined with local thresholding in post-image processing, we were able to successfully eliminate the preliminary calibration process and reduce the burden of overall image processing for image reconstruction in a high-resolution fiberscope. • Binarization is applied to eliminate a calibration used as pre-image processing. • Binarization can reduce the complexity of implementing core peak detection. • Binarization reduces overall image processing time. • Binarization with local thresholding proposed by Bernsen is best for our fiberscope images. • Dynamic method can be applied to image sequencing with further simplification of the process. [ABSTRACT FROM AUTHOR]

This meta-analysis aims to evaluate the trend, methodological quality and completeness of studies on intracellular delivery of antimicrobial agents. PubMed, Embase, and reference lists of related reviews were searched to identify original articles that evaluated carrier-mediated intracellular delivery and pharmacodynamics (PD) of antimicrobial therapeutics against intracellular pathogens in vitro and/or in vivo. A total of 99 studies were included in the analysis. The most commonly targeted intracellular pathogens were bacteria (62.6%), followed by viruses (16.2%) and parasites (15.2%). Twenty-one out of 99 (21.2%) studies performed neither microscopic imaging nor flow cytometric analysis to verify that the carrier particles are present in the infected cells. Only 31.3% of studies provided comparative inhibitory concentrations against a free drug control. Approximately 8% of studies, albeit claimed for intracellular delivery of antimicrobial therapeutics, did not provide any experimental data such as microscopic imaging, flow cytometry, and in vitro PD. Future research on intracellular delivery of antimicrobial agents needs to improve the methodological quality and completeness of supporting data in order to facilitate clinical translation of intracellular delivery platforms for antimicrobial therapeutics. [ABSTRACT FROM AUTHOR]

Agonists of the cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway, a critical mediator of innate immune response to foreign invaders with DNA, have gained significant interest in cancer immunotherapy. STING agonists are envisioned as a way of complementing the antitumor activity of the patient's immune system and immune checkpoint blockade therapy. However, their clinical development has been challenging due to the poor pharmacokinetic and physicochemical properties. This review discusses drug delivery efforts to circumvent the challenges, their accomplishment, and unmet needs based on the last five years of literature. • STING agonists can enhance cancer immunotherapy. • STING agonists have unfavorable pharmacokinetic and physicochemical properties. • Particles, hydrogels, cells, and antibodies are used to improve STING agonist delivery. [ABSTRACT FROM AUTHOR]

A group of nucleic acids and oligonucleotides play various roles in the innate immune system. They can stimulate pattern recognition receptors to activate innate immune cells, encode immunostimulatory proteins or peptides, or silence specific genes to block negative regulators of immune cells. Given the limitations of current cancer immunotherapy, there has been increasing interest in harnessing innate immune responses by nucleic acids and oligonucleotides. The poor biopharmaceutical properties of nucleic acids and oligonucleotides make it critical to use carriers that can protect them in circulation, retain them in the tumor microenvironment, and bring them to intracellular targets. Therefore, various gene carriers have been repurposed to deliver nucleic acids and oligonucleotides for cancer immunotherapy and improve their safety and activity. Here, we review recent studies that employed carriers to enhance the functions of nucleic acids and oligonucleotides and overall immune responses to cancer, and discuss remaining challenges and future opportunities in the development of nucleic acid-based immunotherapeutics. [Display omitted] [ABSTRACT FROM AUTHOR]

Misuse of prescription opioid drugs is the leading cause of the opioid crisis and overdose-related death. Abuse deterrent formulations (ADFs) have been developed to discourage attempts to tamper with the formulation and alter the ingestion methods. However, abusers develop complex extraction strategies to circumvent the ADF technologies. For comprehensive deterrence of drug abuse, we develop tannic acid nanoparticles (NPs) that protect encapsulated opioids from solvent extraction and thermal challenge (crisping), complementing the existing formulation strategy to deter injection abuse. Here, we develop a hybrid ADF tablet (NP-Tab), consisting of iron-crosslinked tannic acid NPs encapsulating thebaine (model opioid compound), xanthan gum, and chitosan (gel-forming polymers), and evaluate its performance in common abuse conditions. NP-Tab tampered by crushing and suspended in aqueous solvents forms an instantaneous gel, which is difficult to pull or push through a 21-gauge needle. NPs insulate the drug from organic solvents, deterring solvent extraction. NPs also promote thermal destruction of the drug to make crisping less rewarding. However, NP-Tab releases thebaine in the simulated gastric fluid without delay, suggesting that its analgesic effect may be unaffected if consumed orally as prescribed. These results demonstrate that NP-Tab can provide comprehensive drug abuse deterrence, resisting aqueous/organic solvent extraction, injection, and crisping, while retaining its therapeutic effect upon regular usage. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] RNAs are known for versatile functions and therapeutic utility. They have gained significant interest since the approval of several RNA drugs, including COVID-19 mRNA vaccines and therapeutic agents targeting liver diseases. There are increasing expectations for a new class of RNA drugs for broader applications. Successful development of RNA drugs for new applications hinges on understanding their diverse functions and structures. In this review, we explore the last five years of literature to understand current approaches to formulate a spectrum of RNA drugs, focusing on new efforts to expand their applications beyond vaccines and liver diseases. [ABSTRACT FROM AUTHOR]

Various power-constrained contrast enhancement (PCCE) techniques have been applied to an organic light emitting diode (OLED) display for reducing the power demands of the display while preserving the image quality. In this paper, we propose a new deep learning-based PCCE scheme that constrains the power consumption of the OLED displays while enhancing the contrast of the displayed image. In the proposed method, the power consumption is constrained by simply reducing the brightness a certain ratio, whereas the perceived visual quality is preserved as much as possible by enhancing the contrast of the image using a convolutional neural network (CNN). Furthermore, our CNN can learn the PCCE technique without a reference image by unsupervised learning. Experimental results show that the proposed method is superior to conventional ones in terms of image quality assessment metrics such as a visual saliency-induced index (VSI) and a measure of enhancement (EME). [ABSTRACT FROM AUTHOR]

Sustained local delivery of meloxicam by polymeric structures is desirable for preventing subacute inflammation and biofilm formation following tissue incision or injury. Our previous study demonstrated that meloxicam release from hot-melt extruded (HME) poly(ε-caprolactone) (PCL) matrices could be controlled by adjusting the drug content. Increasing drug content accelerated the drug release as the initial drug release generated a pore network to facilitate subsequent drug dissolution and diffusion. In this study, high-resolution micro-computed tomography (HR μCT) and artificial intelligence (AI) image analysis were used to visualize the microstructure of matrices and simulate the drug release process. The image analysis indicated that meloxicam release from the PCL matrix was primarily driven by diffusion but limited by the amount of infiltrating fluid when drug content was low (i.e. , the connectivity of the drug/pore network was poor). Since the drug content is not easy to change when a product has a fixed dose and dimension/geometry, we sought an alternative approach to control the meloxicam release from the PCL matrices. Here, magnesium hydroxide (Mg(OH) 2) was employed as a solid porogen in the drug-PCL matrix so that Mg(OH) 2 dissolved with time in the aqueous environment creating additional pore networks to facilitate local dissolution and diffusion of meloxicam. PCL matrices were produced with a fixed 30 wt% meloxicam loading and variable Mg(OH) 2 loadings from 20 wt% to 50 wt%. The meloxicam release increased in proportion to the Mg(OH) 2 content, resulting in almost complete drug release in 14 d from the matrix with 50 wt% Mg(OH) 2. The porogen addition is a simple strategy to tune drug release kinetics, applicable to other drug-eluting matrices with similar constraints. [Display omitted] • Meloxicam-PCL matrix shows slow drug release due to poor channel connectivity. • Image-based simulation of in vitro release identify factors affecting drug release. • Mg(OH) 2 included in PCL matrix slowly dissolves to generate fluid channels. • Mg(OH) 2 helps control drug release kinetics from polymer matrices. [ABSTRACT FROM AUTHOR]

Nanoparticles are used to deliver anticancer drugs to solid tumors. However, clinical development of nanoparticles is challenging because of their limitations in physicochemical properties, such as low drug loading efficiency and poor circulation stability. Low drug loading not only causes technical difficulty in administration but also increases the amount of co-delivered carrier materials, imposing biological burdens to patients. Poor circulation stability causes loss of pharmacokinetics benefits of nanoparticles. To overcome these challenges, we developed an albumin-coated nanocrystal (NC) formulation of paclitaxel (PTX) with 90% drug loading and high serum stability. The NC was produced by inducing crystallization of PTX in aqueous medium, coating the surface with albumin, and removing extra non-drug ingredients. Among three types of NC produced with different crystallization conditions, NC c rystallized i n the m edium containing Pluronic F -127 then coated with alb umin (“Cim-F-alb”) had the smallest size and the most native albumin, thus showing the most favorable cell interaction profiles (low uptake by J774A.1 macrophages and high uptake by SPARC + B16F10 melanoma cells). Cim-F-alb remained more stable in undiluted serum than Abraxane, a commercial albumin-based PTX nanoparticle formulation, while maintaining comparable cytotoxicity to those of Abraxane and solvent-dissolved PTX. In a mouse model of B16F10 melanoma, Cim-F-alb showed higher antitumor efficacy than Abraxane at the same dose. This study demonstrates the feasibility and benefits of delivering an anticancer drug using a carrier-free nanoparticle formulation with good circulation stability. [ABSTRACT FROM AUTHOR]

Many drugs are poorly water-soluble and suffer from low bioavailability. Metal-phenolic network (MPN), a hydrophilic thin layer such as tannic acid (TA)-FeIII network, has been recently used to encapsulate hydrophobic drugs to improve their bioavailability. However, it remains challenging to synthesize nanocapsules of a wide variety of hydrophobic drugs and to scale up the production in a continuous manner. Here, we present a microfluidic synthesis method to continuously produce TA-FeIII network nanocapsules of hydrophobic drugs. We hypothesize that nanocapsules can continuously be formed only when the microfluidic mixing timescale is shorter than the drug's nucleation timescale. The hypothesis was tested on three hydrophobic drugs - paclitaxel, curcumin, and vitamin D with varying solubility and nucleation timescale. The proposed mechanism was validated by successfully predicting the synthesis outcomes. The microfluidically-synthesized nanocapsules had well-controlled sizes of 100–200 nm, high drug loadings of 40–70%, and a throughput of up to 70 mg hr−1 per channel. The release kinetics, cellular uptake, and cytotoxicity were further evaluated. The effect of coating constituents on nanocapsule properties were characterized. Fe content of nanocapsules was reported. The stability of nanocapsules at different temperatures and pHs were also tested. The results suggest that the present method can provide a quantitative guideline to predictively design a continuous synthesis scheme for hydrophobic drug encapsulation via MPN nanocapsules with scaled-up capability. Tannic acid-FeIII network nanocapsules of hydrophobic drugs can be continuously synthesized by controlling the flow condition of mixing on microfluidic platforms. [Display omitted] • Synthesis of metal-phenolic nanocapsules is translated from batch to microfluidics. • Mechanism of encapsulating of a variety of hydrophobic drugs is established. • Effect of concentrations of coating materials on nanocapsule properties are tested. • Quality control at a throughput of 70 mg hr−1 exhibits scale-up potential. [ABSTRACT FROM AUTHOR]

Poly(lactide- co -glycolide) (PLGA) polymers have been widely used for drug delivery due to their biodegradability and biocompatibility. One of the objectives of encapsulating a drug in PLGA microparticles (MPs) is to achieve an extended supply of the drug through sustained release, which can range from weeks to months. Focusing on the applications needing a relatively short-term delivery, we investigated formulation strategies to achieve a drug release from PLGA MPs for two weeks, using meloxicam as a model compound. PLGA MPs produced by the traditional oil/water (O/W) single emulsion method showed only an initial burst release with minimal increase in later-phase drug release. Alternatively, encapsulating meloxicam as solid helped reduce the initial burst release. The inclusion of magnesium hydroxide [Mg(OH) 2 ] enhanced later-phase drug release by neutralizing the developing acidity that limited the drug dissolution. The variation of solid meloxicam and Mg(OH) 2 quantities allowed for flexible control of meloxicam release, yielding MPs with distinct in vitro release kinetics. When subcutaneously injected into rats, the MPs with relatively slow in vitro drug release kinetics showed in vivo drug absorption profiles consistent with in vitro trend. However, the MPs that rapidly released meloxicam showed an attenuated in vivo absorption, suggesting premature precipitation of fast-released meloxicam. In summary, this study demonstrated the feasibility of controlling drug release from the PLGA MPs over weeks based on the physical state of the encapsulated drug and the inclusion of Mg(OH) 2 to neutralize the microenvironmental pH of the MPs. [Display omitted] • Meloxicam was encapsulated in PLGA microparticles for sustained release over 2 weeks. • Encapsulation of meloxicam in the solid state reduced the initial burst release. • Inclusion of Mg(OH) 2 enhanced drug release in the later phase. • Microparticles showed a consistent trend in in vivo drug absorption as in vitro results when the release was relatively slow. [ABSTRACT FROM AUTHOR]

Carfilzomib (CFZ) is a second-generation proteasome inhibitor effective in blood cancer therapy. However, CFZ has shown limited efficacy in solid tumor therapy due to the short half-life and poor tumor distribution. Albumin-coated nanocrystal (NC) formulation was shown to improve the circulation stability of CFZ, but its antitumor efficacy remained suboptimal. We hypothesize that NC size reduction is critical to the formulation safety and efficacy as the small size would decrease the distribution in the reticuloendothelial system (RES) and selectively increase the uptake by tumor cells. We controlled the size of CFZ-NCs by varying the production parameters in the crystallization-in-medium method and compared the size-reduced CFZ-NCs (z-average of 168 nm, NC 168) with a larger counterpart (z-average of 325 nm, NC 325) as well as the commercial CFZ formulation (CFZ-CD). Both CFZ-NCs showed similar or higher cytotoxicity than CFZ-CD against breast cancer cells. NC 168 showed greater uptake by cancer cells, less uptake by macrophages and lower immune cell toxicity than NC 325 or CFZ-CD. NC 168 , but not NC 325 , showed a similar safety profile to CFZ-CD in vivo. The biodistribution and antitumor efficacy of CFZ-NCs in mice were also size-dependent. NC 168 showed greater antitumor efficacy and tumor accumulation but lower RES accumulation than NC 325 in 4T1 breast cancer model. These results support that NC formulation with an optimal particle size can improve the therapeutic efficacy of CFZ in solid tumors. [Display omitted] • CFZ-NC size was reduced by screening and controlling critical nanocrystallization parameters. • NC 168 were captured less by macrophages but taken up more by cancer cells than NC 325. • NC 168 was better tolerated than NC 325 with a similar safety profile as the marketed formulation. • NC 168 showed significantly lower distribution in the RES organs than NC 325 after systemic administration. • NC 168 showed greater antitumor efficacy and tumor distribution than NC 325 in orthotopic breast cancer model. [ABSTRACT FROM AUTHOR]

[Display omitted] • Nanoparticle (NP) deformability affects multiscale biotransport events from circulation to subcellular trafficking. • NP deformability is measured by atomic force microscopy and other surrogate methods. • Young's moduli of NPs range from several kPa to GPa, depending on the type and measurement condition. • Deformability extends the circulation half-life of NPs and improves their tumor penetration. • Conflicting conclusions are reported in other biotransport events due to confounding NP properties. Deformability is one of the critical attributes of nanoparticle (NP) drug carriers, along with size, shape, and surface properties. It affects various aspects of NP biotransport, ranging from circulation and biodistribution to interactions with biological barriers and target cells. Recent studies report additional roles of NP deformability in biotransport processes, including protein corona formation, intracellular trafficking, and organelle distribution. This review focuses on the literature published in the past five years to update our understanding of NP deformability and its effect on NP biotransport. We introduce different methods of modulating and evaluating NP deformability and showcase recent studies that compare a series of NPs in their performance in biotransport events at all levels, highlighting the consensus and disagreement of the findings. It concludes with a perspective on the intricacy of systematic investigation of NP deformability and future opportunities to advance its control toward optimal drug delivery. [ABSTRACT FROM AUTHOR]

The ongoing coronavirus disease 2019 pandemic and its overlap with the influenza season lead to concerns over severe disease caused by the influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) co‐infections. Using a Syrian hamster co‐infection model with SARS‐CoV‐2 and the pandemic influenza virus A/California/04/2009 (H1N1), we found (a) more severe disease in co‐infected animals, compared to those infected with influenza virus alone but not SARS‐CoV‐2 infection alone; (b) altered haematological changes in only co‐infected animals and (c) altered influenza virus tropism in the respiratory tracts of co‐infected animals. Overall, our study revealed that co‐infection with SARS‐CoV‐2 and influenza virus is associated with altered disease severity and tissue tropism, as well as haematological changes, compared to infection with either virus alone. [ABSTRACT FROM AUTHOR]

Low molecular weight chitosan (LMWC) is a promising polymer for surface modification of nanoparticles (NPs), which can impart both stealth effect and electrostatic interaction with cells at mildly acidic pH of tumors. We previously produced LMWC-coated NPs via covalent conjugation to poly(lactic-co-glycolic) acid (PLGA-LMWC NPs). However, this method had several weaknesses including inefficiency and complexity of the production as well as increased hydrophilicity of the polymer matrix, which led to poor drug release control. Here, we used the dopamine polymerization method to produce LMWC-coated NPs (PLGA-pD-LMWC NPs), where the core NPs were prepared with PLGA that served best to load and retain drugs and then functionalized with LMWC via polydopamine layer. The PLGA-pD-LMWC NPs overcame the limitations of PLGA-LMWC NPs while maintaining their advantages. First of all, PLGA-pD-LMWC NPs attenuated the release of paclitaxel to a greater extent than PLGA-LMWC NPs. Moreover, PLGA-pD-LMWC NPs had a pH-dependent surface charge profile and cellular interactions similar to PLGA-LMWC NPs, enabling acid-specific NP–cell interaction and enhanced drug delivery to cells in weakly acidic environment. Although the LMWC layer did not completely prevent protein binding in serum solution, PLGA-pD-LMWC NPs showed less phagocytic uptake than bare PLGA NPs. [ABSTRACT FROM PUBLISHER]

Purpose: To create poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), where a drug-encapsulating NP core is covered with polyethylene glycol (PEG) in a normal condition but exposes a cell-interactive TAT-modified surface in an environment rich in matrix metalloproteinases (MMPs). Methods: PLGA NPs were modified with TAT peptide (PLGA-pDA-TAT NPs) or dual-modified with TAT peptide and a conjugate of PEG and MMP-substrate peptide (peritumorally activatable NPs, PANPs) via dopamine polymerization. Cellular uptake of fluorescently labeled NPs was observed with or without a pre-treatment of MMP-2 by confocal microscopy and flow cytometry. NPs loaded with paclitaxel (PTX) were tested against SKOV-3 ovarian cancer cells to evaluate the contribution of surface modification to cellular delivery of PTX. Results: While the size and morphology did not significantly change due to the modification, NPs modified with dopamine polymerization were recognized by their dark color. TAT-containing NPs (PLGA-pDA-TAT NPs and PANPs) showed changes in surface charge, indicative of effective conjugation of TAT peptide on the surface. PLGA-pDA-TAT NPs and MMP-2-pre-treated PANPs showed relatively good cellular uptake compared to PLGA NPs, MMP-2-non-treated PANPs, and NPs with non-cleavable PEG. After 3 h treatment with cells, PTX loaded in cell-interactive NPs showed greater toxicity than non-interactive ones as the former could enter cells during the incubation period. However, due to the initial burst drug release, the difference was not as clear as microscopic observation. Conclusions: PEGylated polymeric NPs that could expose cell-interactive surface in response to MMP-2 were successfully created by dual modification of PLGA NPs using dopamine polymerization. [ABSTRACT FROM AUTHOR]

Abstract: The present study was undertaken to determine immune response and protection efficacy of a spike (S) protein fragment containing neutralizing epitopes (4F/4R) of turkey coronavirus (TCoV) by priming with DNA vaccine and boosting with the recombinant protein from the corresponding DNA vaccine gene segment. Turkeys were vaccinated by priming with either one dose (G1-750DP) or two doses (G3-750DDP) of 750μg DNA vaccine expressing 4F/4R S fragment and boosting with one dose of 200μg 4F/4R S fragment. One dose of 100μg DNA vaccine mixed with polyethyleneimine (PEI) and sodium hyaluronate (HA) followed by one dose of 750μg DNA vaccine and one dose of 200μg 4F/4R S fragment were given to the turkeys in group G2-100DPH. After infectious challenge by TCoV, clinical signs and TCoV detected by immunofluorescence antibody (IFA) assay were observed in less number of turkeys in vaccination groups than that in challenge control groups. TCoV viral RNA loads measured by quantitative real-time reverse transcription-PCR were lower in vaccinated turkeys than those in challenge control turkeys. The turkeys in G3-750DDP produced the highest level of TCoV S protein-specific antibody and virus neutralization (VN) titer. Comparing to the turkeys in G1-750DP, significantly less TCoV were detected by IFA in the turkeys in G2-100DPH receiving an extra dose of 100μg DNA mixed with PEI and HA. The results indicated that DNA-prime protein-boost DNA vaccination regimen targeting TCoV S fragment encompassing neutralizing epitopes induced humoral immune response and partially protected turkeys against infectious challenge by TCoV. [Copyright &y& Elsevier]

Abstract: For a non-viral gene delivery system to be clinically effective, it should be non-toxic, compatible with biological components, and highly efficient in gene transfection. With this goal in mind, we investigated the gene delivery efficiency of a ternary complex consisting of DNA, an intracellularly degradable polycation, and sodium hyaluronate (DPH complex). Here, we report that the DPH ternary complex achieved significantly higher transfection efficiency than other polymer systems, especially in the presence of serum. The high transfection efficiency and serum tolerance of DPH are attributed to a unique interplay between CLPEI and HA, which leads to (i) the improved stability of DNA in the extracellular environment and at the early stage of intracellular trafficking and (ii) timely dissociation of the DNA–polymer complex. This study reinforces findings of earlier studies that emphasized each step as a bottleneck for efficient gene delivery; yet, it is the first to show that it is possible to overcome these obstacles simultaneously by taking advantage of two distinctive approaches. [Copyright &y& Elsevier]

Abstract: Postoperative peritoneal adhesions cause pelvic pain, infertility, and potentially lethal bowel obstruction. We have designed and synthesized an injectable hydrogel composed of cross-linkable modified hyaluronic acids (HAs) conjugated to dexamethasone (HAX-DEX), and investigated its anti-inflammatory function. HAX-DEX formed a hydrogel in <1min by cross-linking reactions between aldehyde groups and hydrazide groups. The hydrogel degraded in media over 5 days, releasing dexamethasone slowly over that time, reducing TNF-α and IL-6 production from lipopolysaccharide-stimulated primary mouse macrophages in vitro. HAX-DEX was biocompatible on subcutaneous injection, and caused less inflammation than unmodified cross-linked HA. [Copyright &y& Elsevier]

Abstract: Bioengineering approaches, such as co-cultures of multiple cell types, that aim to mimic the physiological microenvironment may be beneficial for optimizing cell function and for engineering tissues in vitro. This study describes a novel method for preparing a spheroid microarray on microfabricated hydrogels, alone or in co-cultures. Photocrosslinkable chitosan was synthesized and utilized for fabricating hydrogel microstructures through a micromolding process. The chitosan surface was initially cell repellent but became increasingly cell adhesive over time. By using this unique property of chitosan hydrogels, it was possible to generate patterned co-cultures of spheroids and support cells. In this scheme, cells were initially microarrayed within low shear stress regions of microwells. Human hepatoblastoma cells, Hep G2, seeded in these wells formed spheroids with controlled sizes and shapes and stably secreted albumin during the culture period. The change of cell adhesive properties in the chitosan surface facilitated the adhesion and growth of a second cell type, NIH-3T3 fibroblast, and therefore enabled co-cultures of hepatocyte spheroids and fibroblast monolayers. This co-culture system could be a useful platform for studying heterotypic cell–cell interactions, for drug screening, and for developing implantable bioartificial organs. [Copyright &y& Elsevier]

For effective resolution of regional subacute inflammation and prevention of biofouling formation, we have developed a polymeric implant that can release meloxicam, a selective cyclooxygenase (COX)-2 inhibitor, in a sustained manner. Meloxicam-loaded polymer matrices were produced by hot-melt extrusion, with co mmercially available biocompatible polymers, poly(ε-caprolactone) (PCL), poly(lactide-co-glycolide) (PLGA), and poly(ethylene vinyl acetate) (EVA). PLGA and EVA had a limited control over the drug release rate partly due to the acidic microenvironment and hydrophobicity, respectively. PCL allowed for sustained release of meloxicam over two weeks and was used as a carrier of meloxicam. Solid-state and image analyses indicated that the PCL matrices encapsulated meloxicam in crystalline clusters, which dissolved in aqueous medium and generated pores for subsequent drug release. The subcutaneously implanted meloxicam-loaded PCL matrices in rats showed pharmacokinetic profiles consistent with their in vitro release kinetics, where higher drug loading led to faster drug release. This study finds that the choice of polymer platform is crucial to continuous release of meloxicam and the drug release rate can be controlled by the amount of drug loaded in the polymer matrices. [Display omitted] • A meloxicam-loaded polymeric implant was developed for control of local inflammation. • Meloxicam was loaded in three polymeric matrices by hot-melt extrusion. • Of three polymers, PCL allowed for sustained release of meloxicam over two weeks. • Meloxicam was encapsulated in clusters, producing pores in matrices upon dissolution. • In vitro in vivo correlation of meloxicam-loaded PCL matrices was confirmed in rats. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates a link between diabetes and cancer. Selective estrogen receptor modulators (SERMs) may increase diabetes risk via antiestrogen effects. This study investigated incident diabetes risk of SERM treatment and its effects on metastatic cancer and death prevention in breast cancer survivors. This retrospective cohort study included female patients with early-stage breast cancer, treated with or without SERMs, between 2008 and 2020 in a tertiary care hospital in Korea. Four propensity score-matched comparison pairs were designed: SERM use versus non-use, long-term use (≥1500 days) versus non-use, tamoxifen use versus non-use, and toremifene use versus non-use; then, logistic regression analysis was performed for risk analysis. SERMs in general were not associated with an elevated risk of diabetes; however, when used for ≥1500 days, SERMs—especially toremifene—substantially increased diabetes risk in breast cancer patients (OR 1.63, p = 0.048). Meanwhile, long-term SERM treatment was effective at preventing metastatic cancer (OR 0.20, p < 0.001) and death (OR 0.13, p < 0.001). SERM treatment, albeit generally safe and effective, may increase diabetes risk with its long-term use in women with breast cancer. Further studies are required to verify the association between toremifene treatment and incident diabetes. [ABSTRACT FROM AUTHOR]

Inflammation that is not resolved in due course becomes a chronic disease. The treatment of chronic inflammatory diseases involves a long-term use of anti-inflammatory drugs such as corticosteroids and nonsteroidal anti-inflammatory drugs, often accompanied by dose-dependent side effects. Local drug delivery systems have been widely explored to reduce their off-target side effects and the medication frequency, with several products making to the market or in development over the years. However, numerous challenges remain, and drug delivery technology is underutilized in some applications. This review showcases local drug delivery systems in different inflammatory diseases, including the targets well-known to drug delivery scientists (e.g., joints, eyes, and teeth) and other applications with untapped opportunities (e.g., sinus, bladder, and colon). In each section, we start with a brief description of the disease and commonly used therapy, introduce local drug delivery systems currently on the market or in the development stage, focusing on polymeric systems, and discuss the remaining challenges and opportunities in future product development. Unlabelled Image • Summary of polymeric carriers for local delivery of anti-inflammatory drugs • Applications to joints, eyes, teeth, sinus, bladder, colon, and lung • Discusses remaining challenges and new opportunities in local drug delivery. • Challenges in release control, delivery duration, and tissue compatibility • Opportunities in personalized design, carrier combination, and device repurposing [ABSTRACT FROM AUTHOR]

Zwitterionic chitosan (ZWC), a water-soluble succinylated chitosan derivative, has anti-inflammatory activities with therapeutic effects on sepsis and colitis. However, it remains unknown whether ZWC has any influence on skin inflammation. Here, we investigated the role of ZWC in the tape-stripping-induced acute skin inflammation model. Topical application of ZWC to the wounded area significantly reduced skin lesion compared with PBS controls. Since tape-stripping-induced skin inflammation is mediated by neutrophils, we examined if ZWC has any suppressive effects on neutrophil's function. ZWC treatment downregulated the skin recruitment of neutrophils, subsequently reducing inflammatory responses by keratinocytes. ZWC also suppressed LPS-induced inflammatory responses of neutrophils in vitro , indicating a direct effect of ZWC on neutrophils. Moreover, such anti-inflammatory effects of ZWC extended to other immune cells such as basophils in the spleen. Overall, our results support that ZWC may be used as a therapeutic material to control acute skin inflammation. • Zwitterionic chitosan (ZWC) has shown anti-inflammatory activity. • However, the effect of ZWC on skin inflammation is unknown. • Topical ZWC application attenuated acute skin inflammation induced by tape-stripping. • ZWC treatment suppressed neutrophils responsible for acute skin inflammation. • Thus, ZWC is a promising biomaterial to control neutrophil-mediated skin injury. [ABSTRACT FROM AUTHOR]

Despite being a major breakthrough in multiple myeloma therapy, carfilzomib (CFZ, a second-generation proteasome inhibitor drug) has been largely ineffective against solid cancer, possibly due to its pharmacokinetic drawbacks including metabolic instability. Recently, quinic acid (QA, a low-affinity ligand of selectins upregulated in peritumoral vasculature) was successfully utilized as a surface modifier for nanoparticles containing paclitaxel. Here, we designed QA-conjugated nanoparticles containing CFZ (CFZ@QANP; the surface of poly(lactic-co-glycolic acid) nanoparticles modified by conjugation with a QA derivative). Compared to the clinically used cyclodextrin-based formulation (CFZ-CD), CFZ@QANP enhanced the metabolic stability and in vivo exposure of CFZ in mice. CFZ@QANP, however, showed little improvement in suppressing tumor growth over CFZ-CD against the murine 4T1 orthotopic breast cancer model. CFZ@QANP yielded no enhancement in proteasomal inhibition in excised tumors despite having a higher level of remaining CFZ than CFZ-CD. These results likely arise from delayed, incomplete CFZ release from CFZ@QANP as observed using biorelevant media in vitro. These results suggest that the applicability of QANP may not be predicted by physicochemical parameters commonly used for formulation design. Our current results highlight the importance of considering drug release kinetics in designing effective CFZ formulations for solid cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Gene expression data is widely used for identifying subtypes of diseases such as cancer. Differentially expressed gene analysis and gene set enrichment analysis are widely used for identifying biological mechanisms at the gene level and gene set level, respectively. However, the results of differentially expressed gene analysis are difficult to interpret and gene set enrichment analysis does not consider the interactions among genes in a gene set. Results: We present CONFIGURE, a pipeline that identifies context specific regulatory modules from gene expression data. First, CONFIGURE takes gene expression data and context label information as inputs and constructs regulatory modules. Then, CONFIGURE makes a regulatory module enrichment score (RMES) matrix of enrichment scores of the regulatory modules on samples using the single-sample GSEA method. CONFIGURE calculates the importance scores of the regulatory modules on each context to rank the regulatory modules. We evaluated CONFIGURE on the Cancer Genome Atlas (TCGA) breast cancer RNA-seq dataset to determine whether it can produce biologically meaningful regulatory modules for breast cancer subtypes. We first evaluated whether RMESs are useful for differentiating breast cancer subtypes using a multi-class classifier and one-vs-rest binary SVM classifiers. The multi-class and one-vs-rest binary classifiers were trained using the RMESs as features and outperformed baseline classifiers. Furthermore, we conducted literature surveys on the basal-like type specific regulatory modules obtained by CONFIGURE and showed that highly ranked modules were associated with the phenotypes of basal-like type breast cancers. Conclusions: We showed that enrichment scores of regulatory modules are useful for differentiating breast cancer subtypes and validated the basal-like type specific regulatory modules by literature surveys. In doing so, we found regulatory module candidates that have not been reported in previous literature. This demonstrates that CONFIGURE can be used to predict novel regulatory markers which can be validated by downstream wet lab experiments. We validated CONFIGURE on the breast cancer RNA-seq dataset in this work but CONFIGURE can be applied to any gene expression dataset containing context information. [ABSTRACT FROM AUTHOR]

Carfilzomib (CFZ) is the second-in-class proteasome inhibitor with much improved efficacy and safety profiles over bortezomib in multiple myeloma patients. In expanding the utility of CFZ to solid cancer therapy, the poor aqueous solubility and in vivo instability of CFZ are considered major drawbacks. We investigated whether a nanocrystal (NC) formulation can address these issues and enhance anticancer efficacy of CFZ against breast cancer. The surface of NC was coated with albumin in order to enhance the formulation stability and drug delivery to tumors via interactions with albumin-binding proteins located in and near cancer cells. The novel albumin-coated NC formulation of CFZ (CFZ-alb NC) displayed improved metabolic stability and enhanced cellular interactions, uptake and cytotoxic effects in breast cancer cells in vitro. Consistently, CFZ-alb NC showed greater anticancer efficacy in a murine 4T1 orthotopic breast cancer model than the currently used cyclodextrin-based formulation. Overall, our results demonstrate the potential of CFZ-alb NC as a viable formulation for breast cancer therapy. Unlabelled Image [ABSTRACT FROM AUTHOR]