Machine learning algorithms for prediction of entrapment efficiency in nanomaterials.

Exploitation of machine learning in predicting performance of nanomaterials is a rapidly growing dynamic area of research. For instance, incorporation of therapeutic cargoes into nanovesicles (i.e., entrapment efficiency) is one of the critical parameters that ensures proper entrapment of drugs in the developed nanosystems. Several factors affect the entrapment efficiency of drugs and thus multiple assessments are required to ensure drug retention, and to reduce cost and time. Supervised machine learning can allow for the construction of algorithms that can mine data available from earlier studies to predict performance of specific types of nanoparticles. Comparative studies that utilize multiple regression algorithms to predict entrapment efficiency in nanomaterials are scarce. Herein, we report on a detailed methodology for prediction of entrapment efficiency in nanomaterials (e.g., niosomes) using different regression algorithms (i.e., CatBoost, linear regression, support vector regression and artificial neural network) to select the model that demonstrates the best performance for estimation of entrapment efficiency. The study concluded that CatBoost algorithm demonstrated the best performance with maximum R2 score (0.98) and mean square error (< 10-4). Among the various parameters that possess a role in entrapment efficiency of drugs into niosomes, the results obtained from CatBoost model revealed that the drug:lipid ratio is the major contributing factor affecting entrapment efficiency, followed by the lipid:surfactant molar ratio. Hence, supervised machine learning may be applied for future selection of the components of niosomes that achieve high entrapment efficiency of drugs while minimizing experimental procedures and cost.

Methods for preparation of niosomes: A focus on thin-film hydration method.

Development of nanocarriers has opened new avenues for the delivery of therapeutics of various pharmacological activities with improved targeting properties and reduced side effects. Niosomes, non-ionic-based vesicles, have drawn much interest in various biomedical applications, owing to their unique characteristics and their ability to encapsulate both hydrophilic and lipophilic cargoes. Niosomes share structural similarity with liposomes while overcoming limitations associated with stability, sterilization, and large-scale production of liposomes. Different methods for preparation of niosomes have been described in the literature, each having its own merits and a great impact on the sizes and characteristics of the formed niosomes. In this article, procedures involved in the thin-film hydration method, a commonly used method for the preparation of niosomes, are described in detail, while highlighting precautions that should be considered for consistent and reproducible construction of niosomes.

Methods for preparation of nanostructured lipid carriers.

Construction of nanocarriers of different structures and properties have shown great promise as delivery systems for a wide range of drugs to improve therapeutic effects and reduce side effects. Nanostructured lipid carriers (NLCs) have been introduced as a new generation of solid lipid nanoparticles (SLNs) to overcome several of the limitations associated with the SLNs. NLCs consist of a blend of solid and liquid lipids which result in a partially crystallized lipid system that enables higher drug loading efficiency compared to SLNs. Owing to their biocompatibility, low toxicity, ease of preparation and scaling-up, and high stability, NLCs have been exploited in numerous pharmaceutical applications. Different methods for fabrication of NLCs have been described in the literature. In this article, procedures involved in emulsification-solvent evaporation method, one of the commonly utilized methods for preparation of NLCs, are described in detail. Critical aspects that should be considered throughout preparation process are also highlighted to allow for consistent and reproducible construction of NLCs.

Multiple analyte profiling (MAP) index as a powerful diagnostic and therapeutic monitoring tool.

A robust data mining algorithm is presented as a critical solution to the challenge of managing intensive data generated from the recently developed multiplexing techniques, which allow simultaneous detection of up to 500 biomarkers in a few microliters of a single sample. Furthermore, detailed methodology is provided for exploiting the new algorithm along with examples for description of the first application as a powerful diagnostic and therapeutic monitoring tool in the management of breast cancer, as a disease model.

Morphologic design of nanostructures for enhanced antimicrobial activity.

Despite significant progress in synthetic polymer chemistry and in control over tuning the structures and morphologies of nanoparticles, studies on morphologic design of nanomaterials for the purpose of optimizing antimicrobial activity have yielded mixed results. When designing antimicrobial materials, it is important to consider two distinctly different modes and mechanisms of activity-those that involve direct interactions with bacterial cells, and those that promote the entry of nanomaterials into infected host cells to gain access to intracellular pathogens. Antibacterial activity of nanoparticles may involve direct interactions with organisms and/or release of antibacterial cargo, and these activities depend on attractive interactions and contact areas between particles and bacterial or host cell surfaces, local curvature and dynamics of the particles, all of which are functions of nanoparticle shape. Bacteria may exist as spheres, rods, helices, or even in uncommon shapes (e.g., box- and star-shaped) and, furthermore, may transform into other morphologies along their lifespan. For bacteria that invade host cells, multivalent interactions are involved and are dependent upon bacterial size and shape. Therefore, mimicking bacterial shapes has been hypothesized to impact intracellular delivery of antimicrobial nanostructures. Indeed, designing complementarities between the shapes of microorganisms with nanoparticle platforms that are designed for antimicrobial delivery offers interesting new perspectives toward future nanomedicines. Some studies have reported improved antimicrobial activities with spherical shapes compared to non-spherical constructs, whereas other studies have reported higher activity for non-spherical structures (e.g., rod, discoid, cylinder, etc.). The shapes of nano- and microparticles have also been shown to impact their rates and extents of uptake by mammalian cells (macrophages, epithelial cells, and others). However, in most of these studies, nanoparticle morphology was not intentionally designed to mimic specific bacterial shape. Herein, the morphologic designs of nanoparticles that possess antimicrobial activities per se and those designed to deliver antimicrobial agent cargoes are reviewed. Furthermore, hypotheses beyond shape dependence and additional factors that help to explain apparent discrepancies among studies are highlighted.

Morphologic Design of Silver-Bearing Sugar-Based Polymer Nanoparticles for Uroepithelial Cell Binding and Antimicrobial Delivery.

Platelet-like and cylindrical nanostructures from sugar-based polymers are designed to mimic the aspect ratio of bacteria and achieve uroepithelial cell binding and internalization, thereby improving their potential for local treatment of recurrent urinary tract infections. Polymer nanostructures, derived from amphiphilic block polymers composed of zwitterionic poly(d-glucose carbonate) and semicrystalline poly(l-lactide) segments, were constructed with morphologies that could be tuned to enhance uroepithelial cell binding. These nanoparticles exhibited negligible cytotoxicity, immunotoxicity, and cytokine adsorption, while also offering substantial silver cation loading capacity, extended release, and in vitro antimicrobial activity (as effective as free silver cations) against uropathogenic Escherichia coli. In comparison to spherical analogues, cylindrical and platelet-like nanostructures engaged in significantly higher association with uroepithelial cells, as measured by flow cytometry; despite their larger size, platelet-like nanostructures maintained the capacity for cell internalization. This work establishes initial evidence of degradable platelet-shaped nanostructures as versatile therapeutic carriers for treatment of epithelial infections.

Ameliorative effect of chitosan nanoparticles against carbon tetrachloride-induced nephrotoxicity in Wistar rats.

CONTEXT: Chitosan is a biocompatible polysaccharide that has been widely exploited in biomedical and drug delivery applications. OBJECTIVE: This study explores the renoprotective effect of chitosan nanoparticles in vivo in rats. MATERIALS AND METHODS: Chitosan nanoparticles were prepared via ionotropic gelation method, and several in vitro characterizations were performed, including measurements of particle size, zeta potential, polydispersity index, Fourier transform-infrared spectroscopy, differential scanning calorimetry, and transmission electron microscopy (TEM) imaging. Wistar rats were divided randomly into four groups; negative control, CCl4-induced nephrotoxicity (untreated), and two groups receiving CCl4 + chitosan NPs (10 and 20 mg/kg) orally for 2 weeks. The renoprotective effect was assessed by measuring oxidative, apoptotic, and inflammatory biomarkers, and via histopathological and immunohistochemical examinations for the visualization of NF-κB and COX-2 in renal tissues. RESULTS: Monodisperse spherical nanosized (56 nm) particles were successfully prepared as evidenced by dynamic light scattering and TEM. Oral administration of chitosan nanoparticles (10 and 20 mg/kg) concurrently with CCl4 for 2 weeks resulted in 13.6% and 21.5% reduction in serum creatinine and increase in the level of depleted reduced glutathione (23.1% and 31.8%), respectively, when compared with the positive control group. Chitosan nanoparticles (20 mg/kg) revealed a significant (p ˂ 0.05) decrease in malondialdehyde levels (30.6%), tumour necrosis factor-α (33.6%), interleukin-1ß (31.1%), and caspase-3 (36.6%). CONCLUSIONS: Chitosan nanoparticles afforded significant protection and amelioration against CCl4-induced nephrotoxicity. Thus, chitosan nanoparticles could afford a potential nanotherapeutic system for the management of nephrotoxicity which allows for broadening their role in biomedical delivery applications.

Design and Preclinical Evaluation of Chitosan/Kaolin Nanocomposites with Enhanced Hemostatic Efficiency.

In the current study, hemostatic compositions including a combination of chitosan and kaolin have been developed. Chitosan is a marine polysaccharide derived from chitins, a structural component in the shells of crustaceans. Both chitosan and kaolin have the ability to mediate a quick and efficient hemostatic effect following immediate application to injury sites, and thus they have been widely exploited in manufacturing of hemostatic composites. By combining more than one hemostatic agent (i.e., chitosan and kaolin) that act via more than one mechanism, and by utilizing different nanotechnology-based approaches to enhance the surface areas, the capability of the dressing to control bleeding was improved, in terms of amount of blood loss and time to hemostasis. The nanotechnology-based approaches utilized to enhance the effective surface area of the hemostatic agents included the use of Pluronic nanoparticles, and deposition of chitosan micro- and nano-fibers onto the carrier. The developed composites effectively controlled bleeding and significantly improved hemostasis and survival rates in two animal models, rats and rabbits, compared to conventional dressings and QuikClot® Combat Gauze. The composites were well-tolerated as demonstrated by their in vivo biocompatibility and absence of clinical and biochemical changes in the laboratory animals after application of the dressings.

Nanoparticles integrating natural and synthetic polymers for in vivo insulin delivery.

The aims of the current study were to develop insulin-loaded nanoparticles comprised of various polymers at different compositions, and to evaluate their ability to lower blood glucose levels in diabetic rats following subcutaneous and oral administrations. Several combinations of natural and synthetic polymers have been utilized for preparation of nanoparticles including, chitosan, alginate, albumin and Pluronic. Nanosized (170 nm-800 nm) spherical particles of high encapsulation efficiency (15-52%) have been prepared. Composition and ratios between the integrated polymers played a pivotal role in determining size, zeta potential, and in vivo hypoglycemic activity of particles. After subcutaneous and oral administration in diabetic rats, some of the insulin-loaded nanoparticles were able to induce much higher hypoglycemic effect as compared to the unloaded free insulin. For instance, subcutaneous injection of nanoparticles comprised of chitosan combined with sodium tripolyphosphate, Pluronic or alginate/calcium chloride, resulted in comparable hypoglycemic effects to free insulin, at two-fold lower dose. Nanoparticles were well-tolerated after oral administration in rats, as evidenced by by measuring levels of alanine aminotransferase, aspartate aminotransferases, albumin, creatinine and urea. This study indicates that characteristics and delivery efficiency of nanomaterials can be controlled via utilizing several natural/synthetic polymers and by fine-tuning of combination ratio between polymers.

Effects of Glutathione and Histidine on NO Release from a Dimeric Dinitrosyl Iron Complex (DNIC).

Rates of NO release from synthetic dinitrosyl iron complexes (DNICs) are shown to be responsive to coordination environments about iron. The effect of biologically relevant cellular components, glutathione and histidine, on the rate of NO release from a dimeric, "Roussin's Red Ester", DNIC with bridging µ-S thioglucose ligands, SGlucRRE or [(µ-SGluc)Fe(NO)2]2 (SGluc = 1-thio-ß-d-glucose tetraacetate), was investigated. From the Griess assay and X-band EPR data, decomposition of the product from the histidine-cleaved dimer, [(SGluc)(NHis)Fe(NO)2], generated Fe(III) and increased the NO release rate in aqueous media when compared to the intact SGlucRRE precursor. In contrast, increasing concentrations of exogenous glutathione generated the stable [(SGluc)(GS)Fe(NO)2]- anion and depressed the rate of NO release. Both of the cleaved, monomeric intermediates were characterized with ESI-MS, EPR, and FT-IR spectroscopies. On the basis of the Griess assay coupled with data from an intracellular fluorometric probe, both the monomeric DNICs and dimeric SGlucRRE diffuse into smooth muscle cells, chosen as appropriate archetypes of vascular relaxation, and release their NO payload. Ultimately, this work provides insight into tuning NO release beyond the design of DNICs, through the incubation with safe, accessible biological molecules.

Multiplexing techniques for measurement of the immunomodulatory effects of particulate materials: Precautions when testing micro- and nano-particles.

Particulate materials at nano- and micro-scales have widespread pharmaceutical and medical applications. Understanding the interactions of these materials with biological systems is crucial for the design of clinically-viable biomaterials of high safety profiles. Immunomodulatory effects of particulate materials can be studied via multiplexing techniques that are capable of measuring up to 500 biomarkers in a few microliters of biological samples. However, there are several challenges towards the use of multiplexing techniques for testing the ability of nanomaterials to induce the release of various biomarkers. As one of the potential challenges, the adsorption of biomarkers on surfaces or within internal structures of nano- or micro-particles has been explored to a lesser extent, although it can lead to biased conclusions and data misinterpretation. Herein, we provide technical details on the use of multiplexing techniques for the evaluation of immunomodulatory effects of nanoparticulates. The same principles can also be applied for the assessment of microparticles. Importantly, precautions to avoid artifacts and data misinterpretation, due to interactions between particles and biomarkers, are provided.

Toward the Optimization of Dinitrosyl Iron Complexes as Therapeutics for Smooth Muscle Cells.

In this study, dinitrosyl iron complexes (DNICs) are shown to deliver nitric oxide (NO) into the cytosol of vascular smooth muscle cells (SMCs), which play a major role in vascular relaxation and contraction. Malfunction of SMCs can lead to hypertension, asthma, and erectile dysfunction, among other disorders. For comparison of the five DNIC derivatives, the following protocols were examined: (a) the Griess assay to detect nitrite (derived from NO conversion) in the absence and presence of SMCs; (b) the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium (MTS) assay for cell viability; (c) an immunotoxicity assay to establish if DNICs stimulate immune response; and (d) a fluorometric assay to detect intracellular NO from treatment with DNICs. Dimeric Roussin's red ester (RRE)-type {Fe(NO)2}9 complexes containing phenylthiolate bridges, [(µ-SPh)Fe(NO)2]2 or SPhRRE, were found to deliver NO with the lowest effect on cell toxicity (i.e., highest IC50). In contrast, the RRE-DNIC with the biocompatible thioglucose moiety, [(µ-SGlu)Fe(NO)2]2 (SGlu = 1-thio-ß-d-glucose tetraacetate) or SGluRRE, delivered a higher concentration of NO to the cytosol of SMCs with a 10-fold decrease in IC50. Additionally, monomeric DNICs stabilized by a bulky N-heterocyclic carbene (NHC), namely, 1,3-bis(2,4,6-trimethylphenyl)imidazolidene (IMes), were synthesized and yielded the DNIC complexes SGluNHC, [IMes(SGlu)Fe(NO)2], and SPhNHC, [IMes(SPh)Fe(NO)2]. These oxidized {Fe(NO)2}9 NHC DNICs have an IC50 of ∼7 µM; however, the NHC-based complexes did not transfer NO into the SMC. Per contra, the reduced, mononuclear {Fe(NO)2}10 neocuproine-based DNIC, neoDNIC, depressed the viability of the SMCs, as well as generated an increase of intracellular NO. Regardless of the coordination environment or oxidation state, all DNICs showed a dinitrosyl iron unit (DNIU)-dependent increase in viability. This study demonstrates a structure-function relationship between the DNIU coordination environment and the efficacy of the DNIC treatments.

Functional, Degradable Zwitterionic Polyphosphoesters as Biocompatible Coating Materials for Metal Nanostructures.

A zwitterionic polyphosphoester (zPPE), specifically l-cysteine-functionalized poly(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane (zPBYP), has been developed as a poly(ethylene glycol) (PEG) alternative coating material for gold nanoparticles (AuNPs), the most extensively investigated metal nanoparticulate platform toward molecular imaging, photothermal therapy, and drug delivery applications. Thiol-yne conjugation of cysteine transformed an initial azido-terminated and alkynyl-functionalized PBYP homopolymer into zPBYP, offering hydrolytic degradability, biocompatibility, and versatile reactive moieties for installation of a range of functional groups. Despite minor degradation during purification, zPPEs were able to stabilize AuNPs presumably through multivalent interactions between combinations of the side chain zwitterions (thioether and phosphoester groups of the zPPEs with the AuNPs). 31P NMR studies in D2O revealed ca. 20% hydrolysis of the phosphoester moieties of the repeat units had occurred during the workup and purification by aqueous dialysis at pH 3 over ca. 1 d, as observed by the 31P signal of the phosphotriesters resonating at ca. -0.5 to -1.7 shifting downfield to ca. 1.1 to -0.4 ppm, attributed to transformation to phosphates. Further hydrolysis of side chain and backbone units proceeded to an extent of ca. 75% over the next 2 d in nanopure water (pH 5-6). The NMR degradation results were consistent with the broadening and red-shift of the surface plasmon resonance (SPR) observed by UV-vis spectroscopy of the zPPE-coated AuNPs in water over time. All AuNP formulations in this study, including those with citrate, PEG, and zPPE coatings, exhibited negligible immunotoxicity, as determined by cytokine overexpression in the presence of the nanostructures relative to those in cell culture medium. Notably, the zPPE-coated AuNPs displayed superior antifouling properties, as assessed by the extent of cytokine adsorption relative to both the PEGylated and citrate-coated AuNPs. Taken together, the physicochemical and biological evaluations of zPPE-coated AuNPs in conjunction with PEGylated and citrate-coated analogues indicate the promise of zPPEs as favorable alternatives to PEG coatings, with negligible immunotoxicity, good antifouling performance, and versatile reactive groups that enable the preparation of highly tailored nanomaterials for diverse applications.

Development and in vivo evaluation of chitosan nanoparticles for the oral delivery of albumin.

Albumin is used as a plasma expander in critically ill patients and for several other clinical applications mainly via intravenous infusion. Oral administration of albumin can improve patient compliance although limited oral bioavailability of proteins is still a major challenge. Although nanomaterials have been extensively utilized for improving oral delivery of proteins, albumin has been utilized only as either a model drug or as a carrier for drug delivery. In the current study, for the first time, chitosan nanoparticles have been developed and extensively optimized to improve oral bioavailability of albumin as a therapeutic protein. Several characterizations have been performed for the albumin-loaded nanoparticles (e.g. drug encapsulation efficiency, DSC, FTIR, particle size, zeta potential, morphology, release kinetics, and enzymatic stability). Nanosized spherical particles were prepared and demonstrated high stability over three months either in a powdered form or as suspensions. Sustained release of albumin over time and high enzymatic stability as compared to the free albumin were observed. In vivo, higher serum concentrations of albumin in normal rabbits and cirrhotic rats were attained following oral and intraperitoneal administrations of the albumin-loaded nanoparticles as compared to the free albumin. The nanoparticles developed in the current study might provide efficient nanovehicles for oral administration of therapeutic albumin.

Development of Fully Degradable Phosphonium-Functionalized Amphiphilic Diblock Copolymers for Nucleic Acids Delivery.

To expand the range of functional polymer materials to include fully hydrolytically degradable systems that bear bioinspired phosphorus-containing linkages both along the backbone and as cationic side chain moieties for packaging and delivery of nucleic acids, phosphonium-functionalized polyphosphoester- block-poly(l-lactide) copolymers of various compositions were synthesized, fully characterized, and their self-assembly into nanoparticles were studied. First, an alkyne-functionalized polyphosphoester- block-poly(l-lactide) copolymer was synthesized via a one pot sequential ring opening polymerization of an alkyne-functionalized phospholane monomer, followed by the addition of l-lactide to grow the second block. Second, the alkynyl side groups of the polyphosphoester block were functionalized via photoinitiated thiol-yne radical addition of a phosphonium-functionalized free thiol. The polymers of varying phosphonium substitution degrees were self-assembled in aqueous buffers to afford formation of well-defined core-shell assemblies with an average size ranging between 30 and 50 nm, as determined by dynamic light scattering. Intracellular delivery of the nanoparticles and their effects on cell viability and capability at enhancing transfection efficiency of nucleic acids (e.g., siRNA) were investigated. Cell viability assays demonstrated limited toxicity of the assembly to RAW 264.7 mouse macrophages, except at high polymer concentrations, where the polymer of high degree of phosphonium functionalization induced relatively higher cytotoxicity. Transfection efficiency was strongly affected by the phosphonium-to-phosphate (P+/P-) ratios of the polymers and siRNA, respectively. The AllStars Hs Cell Death siRNA complexed to the various copolymers at a P+/P- ratio of 10:1 induced comparable cell death to Lipofectamine. These fully degradable nanoparticles might provide biocompatible nanocarriers for therapeutic nucleic acid delivery.

Poly(glycerol methacrylate)-based degradable nanoparticles for delivery of small interfering RNA.

Nucleic acids therapeutic efficiency is generally limited by their low stability and intracellular bioavailability, and by the toxicity of the carriers used to deliver them to the target sites. Aminated poly(glycerol methacrylate) polymers are biodegradable and pH-sensitive polymers that have been used previously to deliver antisense oligonucleotide and show high transfection efficiency. The purpose of this study is to compare the efficiency and toxicity of aminated linear poly(glycerol methacrylate) (ALT) biodegradable polymer to the most commonly used cationic degradable (i.e. chitosan) and non-degradable (i.e. polyethylenimine (PEI)) polymers for delivery of short interfering RNA (siRNA). ALT, PEI and chitosan polymers were able to form nanosized particles with siRNA. Size, size-distribution and zeta-potential were measured over a wide range of nitrogen-to-phosphate (N/P) ratios, and the stability of the formed nanoparticles in saline and upon freeze-drying was also assessed. No significant cytotoxicity at the range of the tested concentrations of ALT and chitosan nanoparticles was observed, whereas the non-degradable PEI showed significant toxicity in huh-7 hepatocyte-derived carcinoma cell line. The safety profiles of the degradable polymers (ALT and chitosan) over non-degradable PEI were demonstrated in vitro and in vivo. In addition, ALT nanoparticles were able to deliver siRNA in vivo with significantly higher efficiency than chitosan nanoparticles. The results in the present study give evidence of the great implications of ALT nanoparticles in biomedical applications due to their biocompatibility, low cytotoxicity, high stability and simple preparation method.

Nanomedicine in management of hepatocellular carcinoma: Challenges and opportunities.

Hepatocellular carcinoma is the second leading cause of cancer deaths worldwide. It is characterized by unique features that can be utilized for selective and targeted therapy, which aids in preserving healthy tissues from deteriorating effects of traditional chemotherapeutics. In this minireview, a brief overview of recent drug delivery attempts for the management of hepatocellular carcinoma with the aid of nanomedical structures is presented. The beneficial impact of nanomaterials in terms of prolonged retention in blood and target sites, controlled biodistribution and improved stability of the encapsulated payloads, will be described, together with the possibility of incorporating more than one cargo into the same nanostructure. Incorporation of stimuli-responsive components, decoration with targeting moieties and the use of molecularly targeted drugs for treatment of hepatocellular carcinoma are also highlighted.

Data Mining as a Guide for the Construction of Cross-Linked Nanoparticles with Low Immunotoxicity via Control of Polymer Chemistry and Supramolecular Assembly.

The potential immunotoxicity of nanoparticles that are currently being approved, in different phases of clinical trials, or undergoing rigorous in vitro and in vivo characterizations in several laboratories has recently raised special attention. Products with no apparent in vitro or in vivo toxicity may still trigger various components of the immune system unintentionally and lead to serious adverse reactions. Cytokines are one of the useful biomarkers for predicting the effect of biotherapeutics on modulation of the immune system and for screening the immunotoxicity of nanoparticles both in vitro and in vivo, and they were recently found to partially predict the in vivo pharmacokinetics and biodistribution of nanomaterials. Control of polymer chemistry and supramolecular assembly provides a great opportunity for the construction of biocompatible nanoparticles for biomedical clinical applications. However, the sources of data collected regarding immunotoxicities of nanomaterials are diverse, and experiments are usually conducted using different assays under specific conditions. As a result, making direct comparisons nearly impossible, and thus, tailoring the properties of nanomaterials on the basis of the available data is challenging. In this Account, the effects of chemical structure, cross-linking, degradability, morphology, concentration, and surface chemistry on the immunotoxicity of an expansive array of polymeric nanomaterials will be highlighted, with a focus on assays conducted using the same in vitro and in vivo models and experimental conditions. Furthermore, numerical descriptive values have been utilized uniquely to stand for induction of cytokines by nanoparticles. This treatment of available data provides a simple way to compare the immunotoxicities of various nanomaterials, and the values were found to correlate well with published data. On the basis of the polymeric systems investigated in this study, valuable information has been collected that will aid in the future design of nanomaterials for biomedical applications, including the following: (a) the immunotoxicity of nanomaterials is concentration- and dose-dependent; (b) the synthesis of degradable nanoparticles is essential to decrease toxicity;

Improving paclitaxel delivery: in vitro and in vivo characterization of PEGylated polyphosphoester-based nanocarriers.

Nanomaterials have great potential to offer effective treatment against devastating diseases by providing sustained release of high concentrations of therapeutic agents locally, especially when the route of administration allows for direct access to the diseased tissues. Biodegradable polyphosphoester-based polymeric micelles and shell cross-linked knedel-like nanoparticles (SCKs) have been designed from amphiphilic block-graft terpolymers, PEBP-b-PBYP-g-PEG, which effectively incorporate high concentrations of paclitaxel (PTX). Well-dispersed nanoparticles physically loaded with PTX were prepared, exhibiting desirable physiochemical characteristics. Encapsulation of 10 wt% PTX, into either micelles or SCKs, allowed for aqueous suspension of PTX at concentrations up to 4.8 mg/mL, as compared to <2.0 µg/mL for the aqueous solubility of the drug alone. Drug release studies indicated that PTX released from these nanostructures was defined through a structure-function relationship, whereby the half-life of sustained PTX release was doubled through cross-linking of the micellar structure to form SCKs. In vitro, physically loaded micellar and SCK nanotherapeutics demonstrated IC50 values against osteosarcoma cell lines, known to metastasize to the lungs (CCH-OS-O and SJSA), similar to the pharmaceutical Taxol formulation. Evaluation of these materials in vivo has provided an understanding of the effects of nanoparticle structure-function relationships on intratracheal delivery and related biodistribution and pharmacokinetics. Overall, we have demonstrated the potential of these novel nanotherapeutics toward future sustained release treatments via administration directly to the sites of lung metastases of osteosarcoma.