Sarecycline pharmacokinetics/pharmacodynamics in the hollow-fibre model of Mycobacterium avium complex: so near and yet so far.

BACKGROUND: Poor sustained sputum culture conversion rates with the standard-of-care therapy highlight the need for better drugs to treat Mycobacterium avium complex pulmonary disease (MAC-PD). OBJECTIVE: To determine the pharmacokinetics/pharmacodynamics (PK/PD)-optimized exposure of sarecycline and its potential role in treating MAC-PD. METHODS: We performed MIC studies with MAC ATCC 700898 and 19 clinical isolates and test-tube static concentration-response studies. A dynamic hollow-fibre system model of intracellular MAC (HFS-MAC) study was performed mimicking six human-equivalent sarecycline dose concentration-time profiles to identify the PK/PD optimal exposure of sarecycline for MAC kill. The inhibitory sigmoid maximal effect (Emax) model was used for PK/PD analysis. RESULTS: The sarecycline MIC of MAC ATCC 700898 was 1 mg/L, while the MIC for the 19 clinical strains ranged between 32 and >256 mg/L. The concentration mediating 50% of Emax (EC50) was similar between intracellular and extracellular MAC. In the HFS-MAC, all six sarecycline doses killed intracellular MAC, with an Emax of 1.0 log10 cfu/mL below Day 0 burden (stasis). The sarecycline EC80 (optimal) exposure was identified as AUC0-24/MIC = 139.46. CONCLUSIONS: Sarecycline demonstrated anti-MAC Emax in the HFS-MAC model better than ethambutol but worse than omadacycline (>5 log10 cfu/mL below stasis) in HFS-MAC. However, since currently approved highest oral sarecycline dose achieves an AUC0-24 of 48.2 mg·h/L and MAC MICs are >32 mg/L, the target AUC0-24/MIC of 139.46 is unlikely to be achieved in patients.

Extracellular vesicles production and proteomic cargo varies with incubation time and temperature.

Extracellular vesicles (EVs) are heterogenous populations of proteolipid bi-layered vesicles secreted by cells as an important biological process. EVs cargo can reflect the cellular environmental conditions in which cells grow. The use of serum-free conditioned media to harvest EVs leads to stress-mediated cellular changes with longer incubation time and impacts EV production and functionality. This study aims to explore the role of incubation time and temperature on EV production and proteomic cargo. For this purpose, an optimized ultrafiltration-size exclusion chromatography-based technique is developed, which isolates small EVs ranging from 130 to 220 nm. The result shows higher EVs production in cancerous cells (K7M2) compared to noncancerous cells (NIH/3T3), which increases with longer incubation time and elevated temperature. Mass spectrometry-based proteomic characterization of EVs showed incubation time and temperature-dependent proteomic profile. A set of enriched EV proteins were identified in EVs isolated at nutrient-stress (72 h incubation time) and heat-stress (40 °C incubation temperature) environment. Enrichment of Serpinb1a in EVs isolated in heat stress was further validated via immunoblot. Gene enrichment analysis revealed that enriched EV proteins following nutrient stress were involved in negative regulation of transcription, response to oxidative stress, and protein folding. Likewise, enriched EV proteins following heat stress were involved in oxaloacetate and aspartate metabolism, and glutamate catabolic process. EVs isolated under nutrient stress showed pro-proliferative activity whereas EVs isolated under heat stress showed anti-proliferative activity. Our results show that incubation time and temperature can alter EV production, its proteomic cargo, and functionality, which can be used to design need-based standard isolation parameters for reproducible EV research.

Overcoming Nanoparticle-Mediated Complement Activation by Surface PEG Pairing.

Many PEGylated nanoparticles activate the complement system, which is an integral component of innate immunity. This is of concern as uncontrolled complement activation is potentially detrimental and contributes to disease pathogenesis. Here, it is demonstrated that, in contrast to carboxyPEG2000-stabilized poly(lactic-co-glycolic acid) nanoparticles, surface camouflaging with appropriate combinations and proportions of carboxyPEG2000 and methoxyPEG550 can largely suppress nanoparticle-mediated complement activation through the lectin pathway. This is attributed to the ability of the short, rigid methoxyPEG550 chains to laterally compress carboxyPEG2000 molecules to become more stretched and assume an extended, random coil configuration. As supported by coarse-grained molecular dynamics simulations, these conformational attributes minimize statistical protein binding/intercalation, thereby affecting sequential dynamic processes in complement convertase assembly. Furthermore, PEG pairing has no additional effect on nanoparticle longevity in the blood and macrophage uptake. PEG pairing significantly overcomes nanoparticle-mediated complement activation without the need for surface functionalization with complement inhibitors.

Occupational stress and coping strategy among community health workers of Mangalore Taluk, Karnataka.

BACKGROUND: Understanding the stress related to work among community health workers (CHWs) might be beneficial to plan intercessions to draw in and spur health-care professionals to toil in remote and disadvantaged region as well as to guarantee the quality of care. OBJECTIVES: This study was conducted to determine the prevalence, level, and sources of occupational stress among CHWs and coping strategies adopted by the CHWs. METHODS: This cross-sectional study was conducted from January to April 2019 among 347 CHWs in 16 Primary Health Centres of Mangalore taluk, Karnataka. Occupational Stress Index and the Brief COPE scale were used to assess the stress level and coping strategy, respectively. Descriptive statistics and Chi-square test were used. The P = 0.05 was considered as significant. RESULTS: The prevalence of occupational stress was found to be 40.5%. Stressors such as under participation, powerlessness, low status, and unprofitability were significantly associated with occupational stress. CHWs used various coping strategies such as self-distraction, active coping, denial, substance use, behavioral disengagement, venting, positive reframing, humor, and self-blame to manage their stress. CONCLUSION: Stress intercession programs could be conducted on a regular interval to make CHWs "stress-free". Higher stress level might impede the performance of the workers, and hence addressing this is necessary. Similarly, positive coping strategies, such as active coping, should be promoted to manage stress.

Biomimetic surface modification of discoidal polymeric particles.

The rationale for the design of drug delivery nanoparticles is traditionally based on co-solvent self-assembly following bottom-up approaches or in combination with top-down approaches leading to tailored physiochemical properties to regulate biological responses. However, the optimal design and control of material properties to achieve specific biological responses remain the central challenge in drug delivery research. Considering this goal, we herein designed discoidal polymeric particles (DPPs) whose surfaces are re-engineered with isolated red blood cell (RBC) membranes to tailor their pharmacokinetics. The RBC membrane-coated DPPs (RBC-DPPs) were found to be biocompatible in cell-based in vitro experiments and exhibited extended blood circulation half-life. They also demonstrated unique kinetics at later time points in a mouse model compared to that of bare DPPs. Our results suggested that the incorporation of biomimicry would enable the biomimetic particles to cooperate with systems in the body such as cells and biomolecules to achieve specific biomedical goals.

Drug Delivery Nanoparticles with Locally Tunable Toxicity Made Entirely from a Light-Activatable Prodrug of Doxorubicin.

PURPOSE: A major challenge facing nanoparticle-based delivery of chemotherapy agents is the natural and unavoidable accumulation of these particles in healthy tissue resulting in local toxicity and dose-limiting side effects. To address this issue, we have designed and characterized a new prodrug nanoparticle with controllable toxicity allowing a locally-delivered light trigger to convert the payload of the particle from a low to a high toxicity state. METHODS: The nanoparticles are created entirely from light-activatable prodrug molecules using a nanoprecipitation process. The prodrug is a conjugate of doxorubicin and photocleavable biotin (DOX-PCB). RESULTS: These DOX-PCB nanoparticles are 30 times less toxic to cells than doxorubicin, but can be activated to release pure therapeutic doxorubicin when exposed to 365 nm light. These nanoparticles have an average diameter of around 100 nm and achieve the maximum possible prodrug loading capacity since no support structure or coating is required to prevent loss of prodrug from the nanoparticle. CONCLUSIONS: These light activatable nanoparticles demonstrate tunable toxicity and can be used to facilitate future therapy development whereby light delivered specifically to the tumor tissue would locally convert the nanoparticles to doxorubicin while leaving nanoparticles accumulated in healthy tissue in the less toxic prodrug form.

A review on nanoparticle-based technologies for biodetoxification.

Nanotechnology has gained significant penetration to different fields of medicine including drug delivery, disease interrogation, targeting and bio-imaging. In recent years, efforts have been put forth to assess the use of this technology in biodetoxification. In this review, we will discuss the current status of nanostructured biomaterials/nanoparticle (NP)-based technologies as a candidate biodetoxifying agent. Patient hospitalization due to illicit drug consumption, suicidal attempts and accidental toxin exposure are major challenges in the medical field. Overdoses of drugs/toxic chemicals or exposure to bacterial toxins or poisons are conventionally treated by voiding the stomach, administering activated charcoal or by using specific antidotes, if the toxin is known. Because of the limitations of these methods for safe and effective detoxification, advancements in nanotechnology may offer novel ways in intoxication support by using nanostructured biomaterials, such as liposomes, micellar nanocarriers, liquid crystalline nanoassemblies and ligand-based NPs.

Hierarchically-Structured Magnetic Nanoconstructs with Enhanced Relaxivity and Cooperative Tumor Accumulation.

Iron oxide nanoparticles are formidable multifunctional systems capable of contrast enhancement in magnetic resonance imaging; guidance under remote fields; heat generation; and biodegradation. Yet, this potential is underutilized in that each function manifests at different nanoparticle sizes. Here, sub-micrometer discoidal magnetic nanoconstructs are realized by confining 5 nm ultra-small super-paramagnetic iron oxide nanoparticles (USPIOs) within two different mesoporous structures, made out of silicon and polymers. These nanoconstructs exhibit transversal relaxivities up to ~10 times (r2 ~ 835 (mM·s)-1) higher than conventional USPIOs and, under external magnetic fields, collectively cooperate to amplify tumor accumulation. The boost in r2 relaxivity arises from the formation of mesoscopic USPIO clusters within the porous matrix, inducing a local reduction in water molecule mobility as demonstrated via molecular dynamics simulations. The cooperative accumulation under static magnetic field derives from the large amount of iron that can be loaded per nanoconstuct (up to ~ 65 fg) and the consequent generation of significant inter-particle magnetic dipole interactions. In tumor bearing mice, the silicon-based nanoconstructs provide MRI contrast enhancement at much smaller doses of iron (~ 0.5 mg of Fe/kg animal) as compared to current practice.

Positron emitting magnetic nanoconstructs for PET/MR imaging.

Hybrid PET/MRI scanners have the potential to provide fundamental molecular, cellular, and anatomic information essential for optimizing therapeutic and surgical interventions. However, their full utilization is currently limited by the lack of truly multi-modal contrast agents capable of exploiting the strengths of each modality. Here, we report on the development of long-circulating positron-emitting magnetic nanoconstructs (PEM) designed to image solid tumors for combined PET/MRI. PEMs are synthesized by a modified nano-precipitation method mixing poly(lactic-co-glycolic acid) (PLGA), lipids, and polyethylene glycol (PEG) chains with 5 nm iron oxide nanoparticles (USPIOs). PEM lipids are coupled with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and subsequently chelated to (64)Cu. PEMs show a diameter of 140 ± 7 nm and a transversal relaxivity r2 of 265.0 ± 10.0 (mM × s)(-1), with a r2/r1 ratio of 123. Using a murine xenograft model bearing human breast cancer cell line (MDA-MB-231), intravenously administered PEMs progressively accumulate in tumors reaching a maximum of 3.5 ± 0.25% ID/g tumor at 20 h post-injection. Correlation of PET and MRI signals revealed non-uniform intratumoral distribution of PEMs with focal areas of accumulation at the tumor periphery. These long-circulating PEMs with high transversal relaxivity and tumor accumulation may allow for detailed interrogation over multiple scales in a clinically relevant setting.

Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform.

Efforts to extend nanoparticle residence time in vivo have inspired many strategies in particle surface modifications to bypass macrophage uptake and systemic clearance. Here we report a top-down biomimetic approach in particle functionalization by coating biodegradable polymeric nanoparticles with natural erythrocyte membranes, including both membrane lipids and associated membrane proteins for long-circulating cargo delivery. The structure, size and surface zeta potential, and protein contents of the erythrocyte membrane-coated nanoparticles were verified using transmission electron microscopy, dynamic light scattering, and gel electrophoresis, respectively. Mice injections with fluorophore-loaded nanoparticles revealed superior circulation half-life by the erythrocyte-mimicking nanoparticles as compared to control particles coated with the state-of-the-art synthetic stealth materials. Biodistribution study revealed significant particle retention in the blood 72 h following the particle injection. The translocation of natural cellular membranes, their associated proteins, and the corresponding functionalities to the surface of synthetic particles represents a unique approach in nanoparticle functionalization.

siRNA-chitosan complexes in poly(lactic-co-glycolic acid) nanoparticles for the silencing of aquaporin-1 in cancer cells.

A large number of studies document the strong expression of aquaporin-1 (AQP1) in tumor microvessels and correlate this aberrant expression with higher metastatic potential and aggressiveness of the malignancy. Although small animal experiments have shown that the modulation of AQP1 expression can halt angiogenesis and induce tumor regression, effective and safe strategies for the tissue specific inhibition of AQP1 are still missing. Here, small interference RNA-chitosan complexes encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) are proposed for the intracellular delivery of siRNA molecules against AQP1. These NPs are coated with poly(vinyl alcohol) (PVA), to improve stability under physiological conditions, and demonstrate a diameter of 160 nm. The partial neutralization of the negatively charged siRNA molecules with the cationic chitosan enhances the loading by 5-fold, as compared to that of the free siRNA molecules, and allows one to modulate the release kinetics in the pH-dependent manner. At pH = 7.4, mimicking the conditions found in the systemic circulation, only the 40% of siRNA is released at 24 h post incubation; whereas at pH = 5.0, recreating the cell endosomal environment, all siRNA molecules are released in about 3 h. These NPs show no cytotoxicity on HeLa cells up to 72 h of incubation. In the same cells, transfected to overexpress AQP1, a silencing efficiency of 70% is achieved at 24 h post treatment with siRNA-loaded NPs. Confocal microscopy analysis of NP uptake demonstrates that siRNA molecules accumulate perinuclearly and in the nucleus. Given the stability, preferential release behavior, and well-known biocompatibility properties of PLGA nanostructures, these siRNA-loaded NPs hold potential for the efficient and safe in vivo silencing of AQPs via systemic administration.

Effect of Nanoparticle Weight on the Cellular Uptake and Drug Delivery Potential of PLGA Nanoparticles.

Biodegradable and biocompatible polymeric nanoparticles (NPs) stand out as a key tool for improving drug bioavailability, reducing the inherent toxicity, and targeting the intended site. Most importantly, the ease of polymer synthesis and its derivatization to add functional properties makes them potentially ideal to fulfill the requirements for intended therapeutic applications. Among many polymers, US FDA-approved poly(l-lactic-co-glycolic) acid (PLGA) is a widely used biocompatible and biodegradable co-polymer in drug delivery and in implantable biomaterials. While many studies have been conducted using PLGA NPs as a drug delivery system, less attention has been given to understanding the effect of NP weight on cellular behaviors such as uptake. Here we discuss the synthesis of PLGA NPs with varying NP weights and their colloidal and biological properties. Following nanoprecipitation, we have synthesized PLGA NP sizes ranging from 60 to 100 nm by varying the initial PLGA feed in the system. These NPs were found to be stable for a prolonged period in colloidal conditions. We further studied cellular uptake and found that these NPs are cytocompatible; however, they are differentially uptaken by cancer and immune cells, which are greatly influenced by NPs' weight. The drug delivery potential of these nanoparticles (NPs) was assessed using doxorubicin (DOX) as a model drug, loaded into the NP core at a concentration of 7.0 ± 0.5 wt % to study its therapeutic effects. The results showed that both concentration and treatment time are crucial factors for exhibiting therapeutic effects, as observed with DOX-NPs exhibiting a higher potency at lower concentrations. The observations revealed that DOX-NPs exhibited a higher cellular uptake of DOX compared to the free-DOX treatment group. This will allow us to reduce the recommended dose to achieve the desired effect, which otherwise required a large dose when treated with free DOX. Considering the significance of PLGA-based nanoparticle drug delivery systems, we anticipate that this study will contribute to the establishment of design considerations and guidelines for the therapeutic applications of nanoparticles.

Characterisation of meteorological drought at sub-catchment scale in Afghanistan using station-observed climate data.

Droughts have severely affected Afghanistan over the last four decades, leading to critical food shortages where two-thirds of the country's population are in a food crisis. Long years of conflict have lowered the country's ability to deal with hazards such as drought which can rapidly escalate into disasters. Understanding the spatial and temporal distribution of droughts is needed to be able to respond effectively to disasters and plan for future occurrences. This study used Standardized Precipitation Evapotranspiration Index (SPEI) at monthly, seasonal and annual temporal scales to map the spatiotemporal change dynamics of drought characteristics (distribution, frequency, duration and severity) in Afghanistan. SPEI indices were mapped for river basins, disaggregated into 189 sub-catchments, using monthly precipitation and potential evapotranspiration derived from temperature station observations from 1980 to 2017. The results show these multi-dimensional drought characteristics vary along different years, change among sub-catchments, and differ across temporal scales. During the 38 years, the driest decade and period are 2000s and 1999-2022, respectively. The 2000-01 water year is the driest with the whole country experiencing 'severe' to 'extreme' drought, more than 53% (87 sub-catchments) suffering the worst drought in history, and about 58% (94 sub-catchments) having 'very frequent' drought (7 to 8 months) or 'extremely frequent' drought (9 to 10 months). The estimated seasonal duration and severity present significant variations across the study area and among the study period. The nation also suffers from recurring droughts with varying length and intensity in 2004, 2006, 2008 and most recently 2011. There is a trend towards increasing drought with longer duration and higher severity extending all over sub-catchments from southeast to north and central regions. These datasets and maps help to fill the knowledge gap on detailed sub-catchment scale meteorological drought characteristics in Afghanistan. The study findings improve our understanding of the influences of climate change on the drought dynamics and can guide catchment planning for reliable adaptation to and mitigation against future droughts.

Synthetic graphene-copper nanocomposites interact with the hACE-2 enzyme and inhibit its biochemical activity.

This study demonstrates the copper nanocomposite-induced enzymatic inhibition of human angiotensin I-converting enzyme-2 (hACE-2) by complex stabilization through the formation of the enzyme nanocomposite. The immediate application of this work is related to ACE-2 as a mechanism of SARS-CoV-2 entry into cells. Moreover, ACE-2 enzyme regulation is a potential therapeutic strategy in hypertension and cardiovascular disease, diabetes, lung injury, and fibrotic disorders. Thus, inhibition of ACE-2 with nanocomposite therapy, may have pharmacologic application with regard to infectious and non-infectious diseases. Synthesized copper nanocomposites described here alone with a commercially available compound, were tested for their potential to inhibit hACE-2 activities. Following wet chemical synthesis, Cu/CuO nanoparticles and graphene-copper (GO-Cu) complexes were synthesized and characterized for their chemical integrity. Cu/CuO formed well-dispersed clusters of 390 ± 100 nm, that when complexed with the hACE-2 enzyme exhibited larger clusters of 506 ± 56 nm. The formation of the Cu/CuO and hACE-2 enzyme complex was monitored by analyzing the zeta potential, which reflected the surface charge distribution of the complex. A negatively charged Cu/CuO nanocomposite nearly becomes neutral when complexed with hACE-2 further assuring the complex formation. Formation of this complex and its inactivation of hACE-2 was evaluated using a standardized protocal for enzymatic activity. Similarly, carboxylate-functionalized graphene was complexed with copper, and its inhibitory effect was studied. Each step in the GO-Cu composite formation was monitored by characterizing its surface electrical properties, resulting in a decrease in its zeta potential and conductivity when complexed with copper. The interaction of the nanocomposites with hACE-2 was confirmed by 2D-FDS and gel electrophoresis analysis. GO-Cu was a rapid and efficacious inhibitor compared to Cu-CuO, especially at lower concentrations (2 µg ml-1). Considering the environmental friendliness of copper and graphene and their use in industries as surface coating materials, we anticipate that use of these composites once proven effective, may have future antimicrobial application. Utility of nanocomposites as antimicrobials, either as a surface antimicrobial or as an in vivo therapeutic, could be invisioned for use against current unknown and/or emergent pathogens.

Meropenem-vaborbactam restoration of first-line drug efficacy and comparison of meropenem-vaborbactam-moxifloxacin versus BPaL MDR-TB regimen.

BACKGROUND: Meropenem in combination with ß-lactamase inhibitors (BLIs) and other drugs was tested to identify alternative treatment regimens for multidrug-resistant tuberculosis (MDR-TB). METHODS: The following were performed: (1) MIC experiments; (2) static time-kill studies (STKs) with different BLIs; and (3) a hollow fibre model system of TB (HFS-TB) studies with meropenem-vaborbactam combined with human equivalent daily doses of 20 mg/kg or 35 mg/kg rifampin, or moxifloxacin 400 mg, or linezolid 600 mg vs. bedaquiline-pretonamid-linezolid (BPaL) for MDR-TB. The studies were performed using Mycobacterium tuberculosis (M. tuberculosis) H37Rv and an MDR-TB clinical strain (named M. tuberculosis 16D) that underwent whole genome sequencing. Exponential decline models were used to calculate the kill rate constant (K) of different HFS-TB regimens. RESULTS: Whole genome sequencing revealed mutations associated with resistance to rifampin, isoniazid, and cephalosporins. The meropenem-vaborbactam MIC of M. tuberculosis was H37Rv 2 mg/L and > 128 mg/L for M. tuberculosis 16D. Relebactam and vaborbactam improved both the potency and efficacy of meropenem in STKs. Meropenem-vaborbactam alone failed to kill M. tuberculosis 16D but killed below day 0 burden when combined with isoniazid and rifampin, with the moxifloxacin combination being the most effective and outranking bedaquiline and pretomanid. In the HFS-TB, meropenem-vaborbactam-moxifloxacin and BPaL had the highest K (log10 cfu/mL/day) of 0.31 (95% CI 0.17-0.58) and 0.34 (95% CI 0.21-0.56), while meropenem-vaborbactam-rifampin (35 mg/kg) had a K of 0.18 (95% CI 0.12-0.25). The K for meropenem-vaborbactam-moxifloxacin-linezolid demonstrated antagonism. CONCLUSION: Adding meropenem-vaborbactam could potentially restore the efficacy of isoniazid and rifampin against MDR-TB. The meropenem-vaborbactam-moxifloxacin backbone regimen has implications for creating a new effective MDR-TB regimen.

Large-scale synthesis of lipid-polymer hybrid nanoparticles using a multi-inlet vortex reactor.

Lipid-polymer hybrid nanoparticles combine the advantages of both polymeric and liposomal drug carriers and have shown great promise as a controlled drug delivery platform. Herein, we demonstrate that it is possible to adapt a multi-inlet vortex reactor (MIVR) for use in the large-scale synthesis of these hybrid nanoparticles. Several parameters, including formulation, polymer concentration, and flow rate, are systematically varied, and the effects of each on nanoparticle properties are studied. Particles fabricated from this process display characteristics that are on par with those made on the lab-scale such as small size, low polydispersity, and excellent stability in both PBS and serum. Using this approach, production rates of greater than 10 g/h can readily be achieved, demonstrating that use of the MIVR is a viable method of producing hybrid nanoparticles in clinically relevant quantities.

Indocyanine-type Infrared-820 Encapsulated Polymeric Nanoparticle-Assisted Photothermal Therapy of Cancer.

Organic small-molecule photosensitizers are well-characterized and known for the light-responsive treatment modality including photodynamic therapy. Compared with ultraviolet-visible (UV-vis) light used in conventional photodynamic therapy with organic photosensitizers, near-infrared (NIR) light from 700 to 900 nm is less absorbed and scattered by biological tissue such as hemoglobin, lipids, and water, and thus, the use of NIR excitation can greatly increase the penetration depth and emission. Additionally, NIR light has lower energy than UV-vis that can be beneficial due to less activation of fluorophores present in tissues upon NIR irradiation. However, the low water stability, nonspecific distribution, and short circulation half-life of the organic photosensitizers limit its broad biological application. NIR responsive small-molecule fluorescent agents are the focus of extensive research for combined molecular imaging and hyperthermia. Recently a new class of NIR dye, IR-820 with excitation and emission wavelengths of 710 and 820 nm, has been developed and explored as an alternative platform to overcome some of the limitations of the most commonly used gold nanoparticles for photothermal therapy of cancer. Herein, we synthesized a core-shell biocompatible nanocarrier envelope made up of a phospholipid conjugated with poly(ethylene glycol) as a shell, while poly(lactic glycolic acid) (PLGA) was used as a core to encapsulate IR-820 dye. The IR-820-loaded nanoparticles were prepared by nanoprecipitation and characterized for their physicochemical properties and photothermal efficiency. These nanoparticles were monodispersed and highly stable in physiological pH with the hydrodynamic size of 103 ± 8 nm and polydispersity index of 0.163 ± 0.031. The IR-820-loaded nanocarrier showed excellent biocompatibility in the dark, whereas remarkable phototoxicity was observed with breast cancer cells (MCF-7) upon NIR laser excitation. Therefore, the IR-820-loaded phospholipid mimicking biodegradable lipid-polymer composite nanoparticles could have great potential for cancer theranostics.

Re-engineered imaging agent using biomimetic approaches.

Recent progress in biomedical technology, the clinical bioimaging, has a greater impact on the diagnosis, treatment, and prevention of disease, especially by early intervention and precise therapy. Varieties of organic and inorganic materials either in the form of small molecules or nano-sized materials have been engineered as a contrast agent (CA) to enhance image resolution among different tissues for the detection of abnormalities such as cancer and vascular occlusion. Among different innovative imaging agents, contrast agents coupled with biologically derived endogenous platform shows the promising application in the biomedical field, including drug delivery and bioimaging. Strategy using biocomponents such as cells or products of cells as a delivery system predominantly reduces the toxic behavior of its cargo, as these systems reduce non-specific distribution by navigating its cargo toward the targeted location. The hypothesis is that depending on the original biological role of the naïve cell, the contrast agents carried by such a system can provide corresponding natural designated behavior. Therefore, by combining properties of conventional synthetic molecules and nanomaterials with endogenous cell body, new solutions in the field of bioimaging to overcome biological barriers have been offered as innovative bioengineering. In this review, we will discuss the engineering of cell and cell-derived components as a delivery system for various contrast agents to achieve clinically relevant contrast for diagnosis and study underlining mechanism of disease progression. This article is categorized under: Nanotechnology Approaches to Biology > Cells at the Nanoscale Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Integration of In Vitro and In Vivo Models to Predict Cellular and Tissue Dosimetry of Nanomaterials Using Physiologically Based Pharmacokinetic Modeling.

Nanomaterials (NMs) have been increasingly used in a number of areas, including consumer products and nanomedicine. Target tissue dosimetry is important in the evaluation of safety, efficacy, and potential toxicity of NMs. Current evaluation of NM efficacy and safety involves the time-consuming collection of pharmacokinetic and toxicity data in animals and is usually completed one material at a time. This traditional approach no longer meets the demand of the explosive growth of NM-based products. There is an emerging need to develop methods that can help design safe and effective NMs in an efficient manner. In this review article, we critically evaluate existing studies on in vivo pharmacokinetic properties, in vitro cellular uptake and release and kinetic modeling, and whole-body physiologically based pharmacokinetic (PBPK) modeling studies of different NMs. Methods on how to simulate in vitro cellular uptake and release kinetics and how to extrapolate cellular and tissue dosimetry of NMs from in vitro to in vivo via PBPK modeling are discussed. We also share our perspectives on the current challenges and future directions of in vivo pharmacokinetic studies, in vitro cellular uptake and kinetic modeling, and whole-body PBPK modeling studies for NMs. Finally, we propose a nanomaterial in vitro to in vivo extrapolation via physiologically based pharmacokinetic modeling (Nano-IVIVE-PBPK) framework for high-throughput screening of target cellular and tissue dosimetry as well as potential toxicity of different NMs in order to meet the demand of efficient evaluation of the safety, efficacy, and potential toxicity of a rapidly increasing number of NM-based products.

Bacterial toxin-triggered drug release from gold nanoparticle-stabilized liposomes for the treatment of bacterial infection.

We report a new approach to selectively deliver antimicrobials to the sites of bacterial infections by utilizing bacterial toxins to activate drug release from gold nanoparticle-stabilized phospholipid liposomes. The binding of chitosan-modified gold nanoparticles to the surface of liposomes can effectively prevent them from fusing with one another and from undesirable payload release in regular storage or physiological environments. However, once these protected liposomes "see" bacteria that secrete toxins, the toxins will insert into the liposome membranes and form pores, through which the encapsulated therapeutic agents are released. The released drugs subsequently impose antimicrobial effects on the toxin-secreting bacteria. Using methicillin-resistant Staphylococcus aureus (MRSA) as a model bacterium and vancomycin as a model anti-MRSA antibiotic, we demonstrate that the synthesized gold nanoparticle-stabilized liposomes can completely release the encapsulated vancomycin within 24 h in the presence of MRSA bacteria and lead to inhibition of MRSA growth as effective as an equal amount of vancomycin-loaded liposomes (without nanoparticle stabilizers) and free vancomycin. This bacterial toxin enabled drug release from nanoparticle-stabilized liposomes provides a new, safe, and effective approach for the treatment of bacterial infections. This technique can be broadly applied to treat a variety of infections caused by bacteria that secrete pore-forming toxins.