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Recently, there has been an increasing interest for utilizing the host immune system to fight against cancer. Moreover, cancer vaccines, which can stimulate the host immune system to respond to cancer in the long term, are being investigated as a promising approach to induce tumor-specific immunity. In this work, we prepared an effective cancer vaccine (denoted as vacosome) by reconstructing the cancer cell membrane, monophosphoryl lipid A as a toll-like receptor 4 agonist, and egg phosphatidylcholine. The vacosome triggered and enhanced bone marrow dendritic cell maturation as well as stimulated the antitumor response against breast cancer 4T1 cells in vitro. Furthermore, an immune memory was established in BALB/c mice after three-time preimmunization with the vacosome. After that, the immunized mice showed inhibited tumor growth and prolonged survival period (longer than 50 days). Overall, our results demonstrate that the vacosome can be a potential candidate for clinical translation as a cancer vaccine.

Myocardial infarction results in a massive loss of cardiomyocytes (CMs). Unfortunately, current therapies are unsuccessful in replacing lost CMs, and thus, there is an urgent need for innovative approaches. Here, a nanosystem based on spermine-acetalated dextran (AcDXSp) and encapsulating two drug compounds able to stimulate in vitro CMs proliferation is developed. The nanosystem is coated by deposition of a film constituted by tannic acid (TA) and Fe3+ ions. The coating with TA increases the retention of the nanocarrier in cell co-cultures of CMs and fibroblasts stimulated with transforming growth factor (TGF)-β, due to the high affinity of TA for components of the cardiac extracellular matrix. The system exhibits biocompatibility toward primary CMs and induces their proliferation, as indicated by the two-fold increase of CMs in the active cell cycle. At the same time, the presence of TA synergistically helps contrasting fibrosis by reducing profibrotic genes expression, such as collagen 1 and osteopontin, by approximately 80% compared to the control. Overall, the developed nanosystem demonstrates the capability to stimulate CMs proliferation and reduce fibrosis, showing potential benefits for future in vivo applications.

Nanoparticles are a class of materials incorporating particulate substances and are characterized by a dimension measuring less than 100 nm. They are signified in their influence of their size and shapes on the physicochemical properties of a substance, which in turn influences their absorption properties ( Khan et al., 2019 ). This chapter reviews conventionally used nanoparticles in regenerative dentistry and will explore how these have been optimized to improve long-term outcomes. It is imperative that endodontic pathologies receive a sustained supply of antimicrobial drugs over a long period of time in order to achieve successful treatment outcomes ( Ng et al., 2015 ). The use of nanoparticles ensures these properties improving overall antimicrobial efficacy, even more so using functionalized nanoparticles. Nanoparticles in the endodontics field has been used in a number of applications including tissue regeneration, drug delivery systems, and antimicrobial administration, mainly aimed at improving overall oral health, particularly by eliminating biofilms and bacteria.

Biomaterials capable of transmitting signals over longer distances than those in rigid electronics can open new opportunities for humanity by mimicking the way tissues propagate information. For seamless mirroring of the human body, they also have to display conformability to its curvilinear architecture, as well as, reproducing native-like mechanical and electrical properties combined with the ability to self-heal on demand like native organs and tissues. Along these lines, a multifunctional composite is developed by mixing silk fibroin and reduced graphene oxide. The material is coined "CareGum" and capitalizes on a phenolic glue to facilitate sacrificial and hierarchical hydrogen bonds. The hierarchal bonding scheme gives rise to high mechanical toughness, record-breaking elongation capacity of approximate to 25 000%, excellent conformability to arbitrary and complex surfaces, 3D printability, a tenfold increase in electrical conductivity, and a fourfold increase in Young's modulus compared to its pristine counterpart. By taking advantage of these unique properties, a durable and self-healing bionic glove is developed for hand gesture sensing and sign translation. Indeed, CareGum is a new advanced material with promising applications in fields like cyborganics, bionics, soft robotics, human-machine interfaces, 3D-printed electronics, and flexible bioelectronics.

Correction: Acetalated dextran based nano- and microparticles: synthesis, fabrication, and therapeutic applications Chem. Commun., 2021,57, 4468 DOI: 10.1039/d1cc90141a Acetalated dextran (Ac-DEX) is a pH-responsive dextran derivative polymer. Prepared by a simple acetalation reaction, Ac-DEX has tunable acid-triggered release profile. Despite its relatively short research history, Ac-DEX has shown great potential in various therapeutic applications. Furthermore, the recent functionalization of Ac-DEX makes versatile derivatives with additional properties. Herein, we summarize the cutting-edge development of Ac-DEX and related polymers. Specifically, we focus on the chemical synthesis, nano- and micro-particle fabrication techniques, the controlled-release mechanisms, and the rational design Ac-DEX-based of drug delivery systems in various biomedical applications. Finally, we briefly discuss the challenges and future perspectives in the field.

The progressive development of zeolitic imidazolate frameworks (ZIFs), as a subfamily of metal-organic frameworks (MOFs), and their unique features, including tunable pore size, large surface area, high thermal stability, and biodegradability/biocompatibility, have made them attractive in the field of biomedicine, especially for drug delivery and biomineralization applications. The high porosity of ZIFs gives them the opportunity for encapsulating a high amount of therapeutic drugs, proteins, imaging cargos, or a combination of them to construct advanced multifunctional drug delivery systems (DDSs) with combined therapeutic and imaging capabilities. This review summarizes recent strategies on the design and fabrication of ZIF-based nansystems and their exploration in the biomedical field. First, recent developments for the adjustment of particle size, functionality, and morphology of ZIFs are discussed, which are important for achieving optimized therapeutic/theranostic nanosystems. Second, recent trends on the application of ZIF nanocarriers for the loading of diverse cargos, including anticancer medicines, antibiotic drugs, enzymes, proteins, photosensitizers, as well as imaging and photothermal agents, are investigated in order to understand how multifunctional DDSs can be designed based on the ZIF nanoparticles to treat different diseases, such as cancer and infection. Finally, prospects on the future research direction and applications of ZIF-based nanomedicines are discussed.

Local drug release in close vicinity of solid tumors is a promising therapeutic approach in cancer therapy. Implantable drug delivery systems can be designed to achieve controlled and sustained drug release. In this study, ultrathin porous membranes of silicon wafer were employed as compatible drug reservoir models. An anticancer model drug, curcumin (CUR), was successfully loaded into porous silicon containers (8.94 ± 0.72% w/w), and then, cerium oxide nanocapping was performed on the open pores for drug protection and release rate prolongation. Next, layer-by-layer surface coating of the drug container with anionic (alginate) and cationic (chitosan) polymers rendered pH-responsivity to the device. The drug release profile was studied using reflectometric interference Fourier transform spectroscopy at different pH conditions. It was determined that faster decomposition of the polymeric layers and subsequent CUR release occur in acidic buffer (pH 5.5) compared to a neutral buffer. Various characterization studies, including dynamic light scattering, Fourier transform infrared spectroscopy, scanning and transmission electron microscopy, contact angle measurement, ultraviolet–visible spectroscopy, and X-ray powder diffraction revealed that our system has the required physicochemical properties to serve as a novel pH-sensitive drug delivery implant for cancer therapy.

Polypyrrole is an example of inherently electrically conductive polymer that is employed in the biomedical arena because of its low cost, excellent electroconductive properties, and good biocompatibility. Because many body tissues respond to electrical fields, polypyrrole-based nanocomposites have become an important class of bio-conductive material. Nanocomposites prepared by blending polypyrrole with other biopolymers or nanomaterials show marked improvements in physicochemical, mechanical, and biological properties. The present review outlines the structure and synthesis of polypyrrole, as well as the physical and mechanical properties of polypyrrole-containing nanocomposites. The antimicrobial and antioxidant activities and possible cytotoxicity of these nanocomposites are summarized and critiqued. A survey of the biomedical applications of polypyrrole as biosensors, drug delivery systems, tissue engineering scaffolds, or photo-thermal therapeutic agents is presented to spur further advances in this exciting field of research.

Wound infection is considered a significant challenge in skin injuries. Sprayable antibacterial wound dressings are interesting alternatives to their traditional counterparts because of their facile preparation, ease-of-use, and the possibility of topical delivery of antibacterial materials. Herein, novel sprayable antibacterial dressings are formulated and reported. The dressings were developed by in-situ formation of Ag-nanoparticles (Ag-NPs) using Persian gum (PG) as a carbohydrate polymer. Several tests were conducted to investigate the effect of polymer concentration on the sprayablity, biocompatibility, and antibacterial activity of the dressings (PG/Ag-NPs). Results showed that formulations up to 2 wt.% PG/Ag-NPs could be sprayed properly and form intact films. Antibacterial evaluations also showed biocidal activity of 1% PG/Ag-NPs against Pseudomonas aeruginosa and Staphylococcus aureus. Cytotoxicity and in vivo full-thickness wound healing evaluation confirmed that 1% PG/ Ag-NPs spray was safe and improved wound healing process. All the results confirmed the high potential of formulated sprayable dressings for wound repair.

Aim: To evaluate the chemotherapeutic potential of a novel multifunctional nanocomposite encapsulating both porous silicon (PSi) and gold (Au) nanoparticles in a polymeric nanocomplex. Materials & methods: The nanocomposite was physicochemically characterized and evaluated in vitro for biocompatibility, cellular internalization, endosomolytic properties, cytoplasmatic drug delivery and chemotherapeutic efficacy. Results: The nanocomposites were successfully produced and exhibited adequate physicochemical properties and superior in vitro cyto- and hemocompatibilities. The encapsulation of PSi nanoparticles in the nanocomplexes significantly enhanced their cellular internalization and enabled their endosomal escape, resulting in the efficient cytoplasmic delivery of these nanosystems. Sorafenib-loaded nanocomposites showed a potent in vitro antiproliferative effect on MDA-MB-231 breast cancer cells. Conclusion: The multifunctional nanocomposite herein presented exhibits great potential as a chemotherapeutic nanoplatform.

Bacterial cellulose (BC) was investigated for the first time for the preparation of capsule shells for immediate and sustained release of drugs. The prepared capsule shells were characterized using X-ray diffraction, scanning electron microscopy and Fourier transform infrared spectroscopy. The BC capsule shells were studied for drug release using an USP type-I dissolution apparatus. Irrespective of the drying method and the thickness of the BC sheet, the capsule shells displayed an immediate drug release profile. Moreover, the addition of release-retardant cellulosic polymers sustained the drug release having first-order kinetics for hydroxypropylmethylcellulose and carboxymethyl cellulose sodium with R 2 values of 0.9995 and 0.9954, respectively. Furthermore, these capsules shells remained buoyant in 0.1 N HCl (pH 1.2) solution up to 12 h. This study showed that BC is a promising alternative to gelatin capsules with both immediate and sustained drug release properties depending upon the compositions of the encapsulated materials.

Due to the synergic feature of individual components in hybrid (nano)biomaterials, their application in regenerative medicine has drawn significant attention. Aiming to address all the current challenges of aerogel as a potent scaffold in bone tissue engineering application, we adopted a novel synthesis approach to synergistically improve the pore size regime and mechanical strength in the aerogel. The three-dimensional aerogel scaffold in this study has been synthesized through a versatile one-pot aqueous-based sol-gel hybridization/assembly of organosilane (tetraethyl orthosilicate) and silk fibroin (SF) biopolymer, followed by unidirectional freeze-casting of the as-prepared hybrid gel and supercritical drying. The developed ultralight silica-SF aerogel hybrids demonstrated a hierarchically organized porous structure with interesting honeycomb-shaped micromorphology and microstructural alignment (anisotropy) in varied length scales. The average macropore size of the hybrid aerogel lied in ∼0.5-18 μm and was systematically controlled with freeze-casting conditions. Together with high porosity (91-94%), high Young's modulus (∼4-7 MPa, >3 order of magnitude improvement compared to their pristine aerogel counterparts), and bone-type anisotropy in the mechanical compressive behavior, the silica-SF hybrid aerogel of this study acted as a very competent scaffold for bone tissue formation. The results of in vitro assessments revealed that the silica-SF aerogel is not only cytocompatible and nonhemolytic but also acted as an open porous microenvironment to trigger osteoblast cell attachment, growth, and proliferation on its surface within 14 days of incubation. Moreover, to support the in vitro results, in vivo bone formation within the aerogel implant in the bone defect site was studied. The X-ray radiology and microcomputed tomography analyses confirmed that a significant new bone tissue density formed in the defect site within 25 days of implantation. Also, in vivo toxicology studies showed a zero-toxic impact of the aerogel implant on the blood biochemical and hematological parameters. Finally, the study clearly shows the potential of aerogel as a bioactive and osteoconductive open porous cellular matrix for a successful osseointegration process.

The emergence of nontoxic, eco-friendly, and biocompatible polymers derived from natural sources has added a new and exciting dimension to the development of low-cost and scalable biomaterials for tissue engineering applications. Here, we have developed a mechanically strong and durable hydrogel composed of an eco-friendly biopolymer that exists within the cell walls of fruits and plants. Its trade name is pectin, and it bears many similarities with natural polysaccharides in the native extracellular matrix. Specifically, we have employed a new pathway to transform pectin into a ultraviolet (UV)-cross-linkable pectin methacrylate (PEMA) polymer. To endow this hydrogel matrix with cell differentiation and cell spreading properties, we have also incorporated thiolated gelatin into the system. Notably, we were able to fine-tune the compressive modulus of this hydrogel in the range ∼0.5 to ∼24 kPa: advantageously, our results demonstrated that the hydrogels can support growth and viability for a wide range of three-dimensionally (3D) encapsulated cells that include muscle progenitor (C2C12), neural progenitor (PC12), and human mesenchymal stem cells (hMSCs). Our results also indicate that PEMA-gelatin-encapsulated hMSCs can facilitate the formation of bonelike apatite after 5 weeks in culture. Finally, we have demonstrated that PEMA-gelatin can yield micropatterned cell-laden 3D constructs through UV light-assisted lithography. The simplicity, scalability, processability, tunability, bioactivity, and low-cost features of this new hydrogel system highlight its potential as a stem cell carrier that is capable of bridging the gap between clinic and laboratory.

The rate of Riboflavin (RF) consumption in cancerous cells is interestingly high and this might imply the use of RF ligand in nanocarriers in order to target anticancer drugs into cancer cells. This study aimed to develop a hybrid drug carrier of Doxorubicin (DOX) loaded on RF targeted micelles composed of hydrophobic polylacticglycolic acid (PLGA) and hydrophilic polyethylene glycol (PEG). In this regard, a simultaneous encapsulation of DOX and in-situ micellization as well as the self-assembly of PLGA-PEG-RF molecules were investigated. Moreover, the effects of microfluidic environment and transition metal dichalcogenide (TMD) nanolayers on the micellization properties (e.g., stability, size, and self-assembly interaction energies) of nanocarriers were simulated for the first time. To this purpose, the simulations were performed using two non-microfluidic methods as well as a novel microfluidic one. The molecular simulations revealed that all of the selected TMDs, especially MoSe2, had a great impact on the stability and size of nanocarriers. MoSe2 significantly enhanced the loading capacity as well as the stability of RF-targeted micelles and reduced the size of nanocarriers. Likewise, the results of various analyses demonstrated that the microfluidic method is the most effective way to synthesize nano carriers with higher stability and smaller particle size. Hence, the use of MoSe2 monolayer, micelle containing RF, and microfluidic method were believed to be the best approach in order to improve the quality of micelles. The present work sheds new light on the use of TMDs in the synthesis of smart carriers for cancer treatment.

A time dependent Eulerian thermal/material flow model of friction stir welding was developed and applied to the dissimilar joining of pure copper and aluminum 1050-H16 alloy to investigate the maximum penetration of base metals. Thermal and material flow analysis was done with the assumed velocity field in the stir zone and considering a thermal source of energy obtained from the both Coulomb type of friction and the loss of shear stress in a non-Newtonian viscous behavior of metal flow. The developed model was used to estimate temperature gradient and penetration of material under three different conditions of tool offset and compared with the experimental results. The model shows that the penetration of the base metals is closely related to tool offset. In all of the cases, the metal fixed in the advancing side is copper. Nevertheless, when considering tool offset in the copper side and also when considering tool offset in the aluminum side, penetrating metals are copper and aluminum, respectively. Also, the model shows that the maximum temperature achieved in the base metals significantly depends on the tool offset.

During the last decades, advanced oral delivery systems to enhance the intestinal absorption of widely applicable proteins and peptides, particularly insulin, have been developed. Here, chitosan-conjugated undecylenic acid-modified thermally hydrocarbonized porous silicon nanoparticles (CSUn NPs) are used, which promote the mucoadhesion and cellular interactions, thus boosting the intestinal permeability of insulin. Then, to further potentiate the mucoadhesion and permeability enhancement of chitosan-modified NPs, the surface of the NPs is further modified with either l-cysteine (CYS-CSUn NPs) or a cell-penetrating peptide (CPP-CSUn NPs). CYS-CSUn and CPP-CSUn NPs show 17- and 12-fold increase in the apparent permeability of insulin across cellular intestinal cells, respectively, with significant enhancement in the cellular interactions. The insulin uptake mechanism pathways in intestinal cells from the developed NPs are also unraveled, which demonstrates major involvement of active transport process and electrostatic interactions, along with adsorptive and clathrin-mediated endocytic pathways. Moreover, after oral administration in diabetic rats, CYS-CSUn NPs show 1.86- and 2.03-fold increase in the relative bioavailability of insulin, as compared to empty NPs and oral insulin solution, respectively. In conclusion, this study presents l-cysteine modified CSUn NPs as a promising strategy with the ability to overcome the multiple barriers for oral delivery of insulin.

Herein, the potential of directional freeze-casting techniques as a very generic, green, and straightforward approach for the processing of various functional porous materials is introduced. These materials include 3D monoliths, films, fibers, and microspheres/beads, which are obtained by the assembly of network building blocks originated from cryoassembly of the various aqueous-based systems. The process simply relies on 1) directional freezing of the slurry through contact with a cold surface, 2) maintaining the slurry at the frozen state for a particular time with controlling the freezing parameters and directions, and 3) sublimation of the created ice crystal templates inside the developed structure to translate the ice growth pattern to final porous structure. The materials developed with such a cryogenic process contain a highly complex porous structure, e.g., a hierarchical and well-aligned microstructure in different levels, which renders a high control over the physicochemical and mechanical functionalities. Due to the versatility and controllability of this technique, the process can also be extended for the mimicking of the structures found in natural materials to the bulk materials to assemble bioinspired porous composites with many useful mechanical and physical features. The aim, herein, is to give a brief overview of the recent advances in developing anisotropic porous inorganic, organic, hybrid, and carbonaceous materials with a particular emphasis on materials with biomimicking microstructure using directional ice templating approach and to highlight their recent breakthrough for different high-performance applications. © 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Despite the promise of hydrogel-based stem cell therapies in orthopedics, a significant need still exists for the development of injectable microenvironments capable of utilizing the regenerative potential of donor cells. Indeed, the quest for biomaterials that can direct stem cells into bone without the need of external factors has been the "Holy Grail" in orthopedic stem cell therapy for decades. To address this challenge, we have utilized a combinatorial approach to screen over 63 nanoengineered hydrogels made from alginate, hyaluronic acid, and two-dimensional nanoclays. Out of these combinations, we have identified a biomaterial that can promote osteogenesis in the absence of well-established differentiation factors such as bone morphogenetic protein 2 (BMP2) or dexamethasone. Notably, in our "hit" formulations we observed a 36-fold increase in alkaline phosphate (ALP) activity and a 11-fold increase in the formation of mineralized matrix, compared to the control hydrogel. This induced osteogenesis was further supported by X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, and energy-dispersive X-ray spectroscopy. Additionally, the Montmorillonite-reinforced hydrogels exhibited high osteointegration as evident from the relatively stronger adhesion to the bone explants as compared to the control. Overall, our results demonstrate the capability of combinatorial and nanoengineered biomaterials to induce bone regeneration through osteoinduction of stem cells in a natural and differentiation-factor-free environment.

Liposomes have attracted much attention as the first nanoformulations entering the clinic. The optimization of physicochemical properties of liposomes during nanomedicine development however is time-consuming and challenging despite great advances in formulation development. Here, we present a systematic approach for the rapid size optimization of liposomes. The combination of microfluidics with a design-of-experiment (DoE) approach offers a strategy to rapidly screen and optimize various liposome formulations, i.e., up to 30 liposome formulations in 1 day. Five representative liposome formulations based on clinically approved lipid compositions were formulated using systematic variations in microfluidics flow rate settings, i.e., flow rate ratio (FRR) and total flow rate (TFR). Interestingly, flow rate-dependent DoE models for the prediction of liposome characteristics could be grouped according to lipid-phase transition temperature and surface characteristics. For all formulations, the FRR had a significant impact (p

Bone tissue engineering is considered an alternative approach for conventional strategies available to treat bone defects. In this study, we have developed bone scaffolds composed of hydroxyapaptite (HAp), gelatin and mesoporous silica, all recognized as promising materials in bone tissue engineering due to favorable biocompatibility, osteoconductivity and drug delivery potential, respectively. These materials were coupled with conductive polypyrrole (PPy) polymer to create a novel bone scaffold for regenerative medicine. Conductive and non-conductive scaffolds were made by slurry casting method and loaded with a model antibiotic, vancomycin (VCM). Their properties were compared in different experiments in which scaffolds containing PPy showed good mechanical properties, higher protein adsorption and higher percentage of VCM release over a long duration of time compared to non-conductive scaffolds. Osteoblast cells were perfectly immersed into the gelatin matrix and remained viable for 14 days. Overall, new conductive composite bone scaffolds were created and the obtained results strongly verified the applicability of this conductive scaffold in drug delivery, encouraging its further development in tissue engineering applications.

Interfacial polymerization of uniform template-free nanostructures is very challenging since many factors play determinant roles in the final structure of the resulting nanoassemblies. Here, we present a single oxidative coupling method for the synthesis of different nanoshapes by addition or substitution of a methyl group on aniline monomers to freely alter the mechanism of monomer-to-polymer conversion. Well-defined nanotubes, nanohollows, and solid nanospheres are obtained from aniline, N-methylaniline, and 2-methylaniline polymerizations, respectively. We found that the extent of hydrophobicity and protonation under mild acidic conditions determines the monomers’ arrangement in micelle or droplet form, reactivity, and nucleation mechanism. These can subsequently affect the final morphology through a fusion process to form tubular structures, external flux of monomers to form nanohollows, and intradroplet oxidation to form solid nanospheres. Altered biological responses, such as cytocompatibility, redo...

Nanotechnology based drug delivery systems are anticipated to overcome the persistent challenges in oral protein and peptide administration, and lead to the development of long awaited non-invasive therapies. Herein, an advanced single-step aerosol flow reactor based technology was used to develop a multifunctional site specific dual protein-drug delivery nanosystem. For this purpose, mucoadhesive porous silicon (PSi) nanoparticles encapsulated into a pH-responsive polymeric nanomatrix was developed for advanced oral type 2 diabetes mellitus therapy with an antidiabetic peptide, glucagon like peptide-1 (GLP-1), and the enzyme inhibitor, dipeptidyl peptidase-4 (DPP4). Chitosan surface modification inherited the mucoadhesiveness to the nanosystem which led to enhanced cellular interactions and increased cellular compatibility. An advanced aerosol flow reactor technology was used to encapsulate the chitosan modified nanoparticles into an enteric polymeric nanomatrix. The pH-sensitive polymeric matrix simultaneously prevented the gastric degradation of the encapsulated peptide and also preserved the mucoadhesive functionality of the chitosan-modified PSi nanoparticles in the harsh stomach environment. The multidrug loaded nanosystem showed augmented intestinal permeability of GLP-1, evaluated in an in vitro cell-based intestinal epithelium model, attributed to the permeation enhancer effect of chitosan and inhibition of GLP-1 degradation by the DPP4 inhibitor. The applied technology resulted in the development of a dual-drug delivery nanosystem that synergizes the antidiabetic effect of the loaded peptide and the enzyme inhibitor, thereby indicating high clinical potential of the system and preparation technique.

Multifunctional tailorable composite systems, specifically designed for oral dual-delivery of a peptide (glucagon-like peptide-1) and an enzymatic inhibitor (dipeptidyl peptidase 4 (DPP4)), were assembled through the microfluidics technique. Both drugs were coloaded into these systems for a synergistic therapeutic effect. The systems were composed of chitosan and cell-penetrating peptide modified poly(lactide-co-glycolide) and porous silicon nanoparticles as nanomatrices, further encapsulated in an enteric hydroxypropylmethylcellulose acetylsuccinate polymer. The developed multifunctional systems were pH-sensitive, inherited by the enteric polymer, enabling the release of the nanoparticles only in the simulated intestinal conditions. Moreover, the encapsulation into this polymer prevented the degradation of the nanoparticles' modifications. These nanoparticles showed strong and higher interactions with the intestinal cells in comparison with the nonmodified ones. The presence of DPP4 inhibitor enhanced the peptide permeability across intestinal cell monolayers. Overall, this is a promising platform for simultaneously delivering two drugs from a single formulation. Through this approach peptides are expected to increase their bioavailability and efficiency in vivo both by their specific release at the intestinal level and also by the reduced enzymatic activity. The use of this platform, specifically in combination of the two antidiabetic drugs, has clinical potential for the therapy of type 2 diabetes mellitus.

Herein, we report the production of monodisperse hollow microparticles from three different polymers, namely, pH-responsive acetylated dextran and hypromellose acetate succinate and biodegradable poly(lactic-co-glycolic acid), at varying polymer concentrations using a poly(dimethylsiloxane)-based microfluidic device. Hollow microparticles formed during solvent diffusion into the continuous phase when the polymer close to the interface solidified, forming the shell. In the inner part of the particle, phase separation induced solvent droplet formation, which dissolved the shell, forming a hole and a hollow-core particle. Computational simulations showed that, despite the presence of convective recirculation around the droplet, the mass-transfer rate of the solvent dissolution from the droplet to the surrounding phase was dominated by diffusion. To illustrate the potential use of hollow microparticles, we simultaneously encapsulated two anticancer drugs and investigated their loading and release profiles. In addition, by utilizing different polymer shells and polymer concentrations, the release profiles of the model drugs could be tailored according to specific demands and applications. The high encapsulation efficiency, controlled drug release, unique hollow microparticle structure, small particle size (

A hybrid nanocomposite comprised by porous silicon nanoparticles and a stimuli responsive polymeric material, polyethylene glycol-block-poly(L-histidine), is spontaneously formed by nanoprecipitation in a flow-focusing microfluidic chip. The nanocomposite presents a novel hybrid compound micelle structure with a great robustness for therapeutic applications. Therefore, the nanocomposite is developed and tested as a “smart” multistage drug delivery system (MDDS) in response to some of the current problems that cancer treatment presents. Based on the stimuli-responsive behavior of the nanocomposite, a chemotherapeutic agent is successfully loaded into the nanosystem and released upon changes in the pH-values. The nanocomposite demonstrates enhanced stability in plasma, narrow size distribution, improved surface smoothness, and high cytocompatibility. Furthermore, the nanocomposite presents reduced nanoparticle internalization by phagocytic macrophage cells and pH-dependent cell growth inhibition capacity. Overall, the developed hybrid nanocomposite shows very promising features for its further development as a “smart” pH-responsive MDDS.

Combination therapy via nanoparticulate systems has already been proposed as a synergistic approach for cancer treatment. Herein, undecylenic acid modified thermally hydrocarbonized porous silicon nanoparticles (UnTHCPSi NPs) loaded with sorafenib and surface-biofunctionalized with anti-CD326 antibody (Ab) were developed for cancer chemo-immunotherapy in MCF-7 and MDA-MB-231 breast cancer cells. The cytocompatibility study showed no significant toxicity for the bare and antibody-conjugated UnTHCPSi (Un-Ab) NPs at concentrations lower than 200 μg·mL−1. Compared to the bare UnTHCPSi, Un-Ab NPs loaded with sorafenib reduced the premature drug release in plasma, increasing the probability of proper drug targeting. In addition, high cellular interaction and subsequent internalization of the Un-Ab NPs into the cells expressing CD326 antigen demonstrated the possibility of improving antigen-mediated endocytosis via CD326 targeting. While an in vitro antitumor study revealed a higher inhibitory effect of the sorafenib-loaded Un-Ab NPs compared to the drug-loaded UnTHCPSi NPs in the CD326 positive MCF-7 cells, there was no difference in the anti-proliferation impact of both the abovementioned NPs in the CD326 negative MDA-MB-231 cells, suggesting CD326 as an appropriate receptor for Ab-mediated drug delivery. It was also shown that the anti-CD326 Ab can act as an immunotherapeutic agent by inducing antibody dependent cellular cytotoxicity and enhancing the interaction of effector immune and cancer cells for subsequent phagocytosis and cytokine secretion. Hence, the developed nanovectors can be applied for simultaneous tumor-selective drug targeting and immunotherapy.

In article 1603239, Flavia Fontana, Helder A. Santos, and co-workers develop an innovative cancer nanovaccine by merging the adjuvant properties of the nanoparticles produced by nanoprecipitation in a microfluidic glass capillary device with high reproducibility, together with a biomimetic source of antigens derived from cancer-cell membranes. The nanovectors induce maturation of antigen-presenting cells and secretion of pro-inflammatory cytokines in vitro.

A combined 2D microfluidic-microarray high throughput approach is reported to identify universal bacterial capturing ligands that can be tethered on the surface of 3D sponges fabricated by different methods for concentrating of bacterial targets in diagnosis devices. The developed platform allows for the first time the simultaneous monitoring of various ligands' affinities to different bacteria species in a dynamic condition in vitro. Moreover, it has been feasible to recognize the effect of steric hindrance on the function of capturing motifs through immobilizing spacer molecules with different lengths between the solid surface and ligands. 3D sponges and micropillars are modified with the most potent capturing molecule to assess their bacterial capturing in real blood samples. Next, the 3D structures are placed into a chip with an immense potential to recognize bacteria through imaging and fluorescence intensity concept.

Thermally hydrocarbonized porous silicon (THCPSi) microparticles were loaded with indomethacin (IMC) and griseofulvin (GSV) using three different payloads between 6.2-19.5 and 6.2-11.4 wt %, respectively. The drug loading parameters were selected to avoid crystallization of the drug molecules on the external surface of the particles that would block the pore entrances. The successfulness of the loadings was verified with TG, DSC, and XRPD measurements. The effects of the confinement of IMC and GSV into the small mesopores of THCPSi were analyzed with helium pycnometry, FTIR, and NMR spectroscopy. The results showed the density of the THCPSi loaded drugs to be ca. 10% lower than the bulk crystalline forms, while a melt quenched amorphous drugs showed a density reduction of 3-7.5%. DSC and FTIR results confirmed that the drugs reside in an amorphous form within the THCPSi pores. Similar results were obtained with NMR, which also indicated that IMC may reside as both amorphous clusters and individual molecules within the pores. The (1)H transverse relaxation times (T2) of amorphous and THCPSi loaded drugs showed IMC relaxation times of 0.28 ms for both the cases, whereas for GSV the values were 0.32 and 0.39 ms, respectively, indicating similar limited mobility in both cases. The results indicated that strong drug-carrier interactions were not necessary for stabilizing the amorphous state of the adsorbed drug. Dissolution tests using biorelevant media, fasted state simulated intestinal fluid (FaSSIF) and simulated gastric fluid (SGF), showed that THCPSi-loaded IMC and GSV were rapidly released in FaSSIF with comparable rates to the amorphous forms, whereas in SGF the THCPSi reduced the pH dependency in the dissolution of IMC.

The development of a stable vehicle with low toxicity, high cellular internalization, efficient endosomal escape, and optimal drug release profile is a key bottleneck in nanomedicine. To overcome all these problems, we have developed a successful layer-by-layer method to covalently conjugate polyethyleneimine (PEI) and poly(methyl vinyl ether-co-maleic acid) (PMVE-MA) copolymer on the surface of undecylenic acid functionalized thermally hydrocarbonized porous silicon nanoparticles (UnTHCPSi NPs), forming a bilayer zwitterionic nanocomposite containing free positive charge groups of hyper-branched PEI disguised by the PMVE-MA polymer. The surface smoothness, charge and hydrophilicity of the developed NPs considerably improved the colloidal and plasma stabilities via enhanced suspensibility and charge repulsion. Furthermore, despite the surface negative charge of the bilayer polymer-conjugated NPs, the cellular trafficking and endosomal escape were significantly increased in both MDA-MB-231 and MCF-7 breast cancer cells. Remarkably, we also showed that the conjugation of surface free amine groups of the highly toxic UnTHCPSi-PEI (Un-P) NPs to the carboxylic groups of PMVE-MA renders acceptable safety features to the system and preserves the endosomal escape properties via proton sponge mechanism of the free available amine groups located inside the hyper-branched PEI layer. Moreover, the double layer protection not only controlled the aggregation of the NPs and reduced the toxicity, but also sustained the drug release of an anticancer drug, methotrexate, with further improved cytotoxicity profile of the drug-loaded particles. These results provide a proof-of-concept evidence that such zwitterionic polymer-based PSi nanocomposites can be extensively used as a promising candidate for cytosolic drug delivery.

Porous silicon (PSi) based particulate systems are emerging as an important drug delivery system due to its advantageous properties such as biocompatibility, biodegradability and ability to tailor the particles' physicochemical properties. Here, annealed thermally hydrocarbonized PSi (AnnTHCPSi) and undecylenic acid modified AnnTHCPSi (AnnUnTHCPSi) microparticles were developed as a PSi-based platform for oral delivery of insulin. Chitosan (CS) was used to modify the AnnUnTHCPSi microparticles to enhance the intestinal permeation of insulin. Surface modification with CS led to significant increase in the interaction of PSi microparticles with Caco-2/HT-29 cell co-culture monolayers. Compared to pure insulin, the CS-conjugated microparticles significantly improved the permeation of insulin across the Caco-2/HT-29 cell monolayers, with ca. 20-fold increase in the amount of insulin permeated and ca. 7-fold increase in the apparent permeability (P(app)) value. Moreover, among all the investigated particles, the CS-conjugated microparticles also showed the highest amount of insulin associated with the mucus layer and the intestinal Caco-2 cells and mucus secreting HT-29 cells. Our results demonstrate that CS-conjugated AnnUnTHCPSi microparticles can efficiently enhance the insulin absorption across intestinal cells, and thus, they are promising microsystems for the oral delivery of proteins and peptides across the intestinal cell membrane.

A multifunctional nano-in-micro drug delivery platform is developed by conjugating the porous silicon nanoparticles with mucoadhesive polymers and subsequent encapsulation into a pH-responsive polymer using microfluidics. The multistage platform shows monodisperse size distribution and pH-responsive payload release, and the released nanoparticles are mucoadhesive. Moreover, this platform is capable of simultaneously loading and releasing multidrugs with distinct properties.

Diatoms are porous silica-based materials obtained from single cell photosynthetic algae. Despite low cost, easy purification process, environmentally safe properties, and rapidly increasing potentials for medical applications, the cytotoxicity of diatoms and the effect on drug permeation of oral formulations have not been studied so far. Herein, we have evaluated the potential of diatom silica microparticles (DSMs) for the delivery of mesalamine and prednisone, which are two commonly prescribed drugs for gastrointestinal (GI) diseases. Transmission electron microscopy analysis of the morphological surface changes of Caco-2/HT-29 monolayers and the cell viability data in colon cancer cells (Caco-2, HT-29 and HCT-116) showed very low toxicity of diatoms at concentrations up to 1000 mg/mL. The mesalamine and prednisone release under simulated GI conditions indicated prolonged release of both drugs from the diatoms. Furthermore, drug permeation across Caco-2/HT-29 co-culture monolayers demonstrated that diatoms are capable to enhance the drug permeability. Overall, this study evaluated DSMs’ cytotoxicity in colon cancer cells and the effect of DSMs on drug permeability across Caco-2/HT-29 monolayers. Our results demonstrate that DSMs can be considered as a non-cytotoxic biomaterial with high potential to improve the mesalamine and prednisone bioavailability by sustaining the drug release and enhancing drug permeability., Financial support from the Academy of Finland (decision numbers 252215 and 256394), the University of Helsinki, the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) grant no. 310892 and the ERDF through the Atlantic Area Transnational Cooperation Programme Project 2011-1/164 MARMED are gratefully acknowledged. T.H. Silva acknowledges the Portuguese Foundation for Science and Technology for a post-doc grant (SFRH/BPD/34704/2007). We thank Prof. Lauri A. Aaltonen (Genome-Scale Biology Program & Department of Medical Genetics, University of Helsinki, Finland) for generously providing the HCT-116 cells and Prof. Bruno Sarmento (INEB - Instituto de Engenharia Biomedica, Porto) for kindly providing the HT-29 cells. Pei Ting Mah (University of Otago, New Zeeland) is acknowledged for technical support with the XRPD instrument.

Zinc oxide (ZnO) nanorods were manufactured using the aqueous chemical growth (ACG) method, and the effect of thermal acetylene treatment on their morphology, chemical composition, and optical properties was investigated. Changes in the elemental content of the treated rods were found to be different than in previous reports, possibly due to the different defect concentrations in the samples, highlighting the importance of synthesis method selection for the process. Acetylene treatment resulted in a significant improvement of the ultraviolet photoluminescence of the rods. The greatest increase in emission intensity was recorded on ZnO rods treated at the temperature of 825 °C. The findings imply that the changes brought on by the treatment are limited to the surface of the ZnO rods. Electronic supplementary material The online version of this article (doi:10.1186/s11671-016-1627-y) contains supplementary material, which is available to authorized users.

Immunoadjuvant porous silicon (PSi)-based nanovaccines are prepared by nanoprecipitation in a glass capillary microfluidics device. Vesicles, derived from cancer cell membranes encapsulating thermally oxidized PSi nanoparticles or PSi-polymer nanosystems binding a model antigen, are biocompatible over a wide range of concentrations, and show immunostimulant properties in human cells, promoting the expression of co-stimulatory signals and the secretion of pro-inflammatory cytokines.

Theranostic nanoparticles are emerging as potent tools for noninvasive diagnosis, treatment, and monitoring of solid tumors. Herein, an advanced targeted and multistimuli responsive theranostic platform is presented for the intracellular triggered delivery of doxorubicin. The system consists of a polymeric-drug conjugate solid nanoparticle containing encapsulated superparamagnetic iron oxide nanoparticles (IO@PNP) and decorated with a tumor homing peptide, iRGD. The production of this nanosystem is based on a pH-switch nanoprecipitation method in organic-free solvents, making it ideal for biomedical applications. The nanosystem shows sufficient magnetization saturation for magnetically guided therapy along with reduced cytotoxicity and hemolytic effects. IO@PNP are largely internalized by endothelial and metastatic cancer cells and iRGD decorated IO@PNP moderately enhance their internalization into endothelial cells, while no enhancement is found for the metastatic cancer cells. Poly(ethylene glycol)-block-poly(histidine) with pH-responsive and proton-sponge properties promotes prompt lysosomal escape once the nanoparticles are endocyted. In addition, the polymer-doxorubicin conjugate solid nanoparticles show both intracellular lysosomal escape and efficient translocation of doxorubicin to the nuclei of the cells via cleavage of the amide bond. Overall, IO@PNP-doxorubicin and the iRGD decorated counterpart demonstrate to enhance the toxicity of doxorubicin in cancer cells by improving the intracellular delivery of the drug carried in the IO@PNP.

Advances in nanotechnology have prompted rapid progress and versatile imaging modalities for diagnostics and treatment of diseases. Molecular imaging is a powerful technique for quantifying physiological changes in vivo using noninvasive imaging probes. These probes are used to image specific cells and tissues within a whole organism. Currently, imaging is an essential part of clinical protocols providing morphological, structural, metabolic and functional information. Using theranostic micro- or nanoparticles, which combine both therapeutic and diagnostic capabilities in one single entity, holds a true promise to propel the biomedical field toward personalized medicine. With this approach, biological processes can be directly and simultaneously monitored with the treatment of the diseases. This mini-review highlights the recent innovative diagnostic imaging aspects of porous silicon (PSi) materials and emphasizes their potential as theranostic platforms and tools for the clinic. Multiple biomedical imaging applications of the PSi materials are also outlined.

Copolymers are among the most promising substances used in the preparation of drug/gene delivery systems. Different categories of copolymers, including block copolymers, graft copolymers, star copolymers and crosslinked copolymers, are of interest in drug delivery. A variety of nanostructures, including polymeric micelles, polymersomes and hydrogels, have been prepared from copolymers and tested successfully for their drug delivery potential. The most recent area of interest in this field is smart nanostructures, which benefit from the stimuli-responsive properties of copolymeric moieties to achieve novel targeted drug delivery systems. Different copolymer applications in drug/gene delivery using nanotechnology-based approaches with particular emphasis on smart nanoparticles are reviewed.

MXene nanosheets have emerged as biocompatible transition metal structures, which illustrate desirable performance for various applications due to their unique structural, physicochemical, and compositional features. MXenes are currently expanding their usage territory from mechanical, optical, chemical, and electronic fields toward biomedical areas. This is mainly originated from their large surface area and strong absorbance in near-infrared region, which in combination with their facile surface functionalization with various polymers or nanoparticles, make them promising nanoplatforms for drug delivery, cancer therapy, precise biosensing and bioimaging. The facile surface modification of the MXenes can mediate the better in vivo performance of them through reduced toxicity, enhanced colloidal stability, and extended circulation within the body. Herein, the synthesis and state-of-the-art progresses of MXene nanosheets designed for biomedical applications, including structural- and dose-dependent antimicrobial activity, photothermal therapy, drug delivery, and implants are emphasized. Furthermore, biosensing applications are highlighted and a comprehensive discussion on photoacoustic imaging, magnetic resonance imaging, computed tomography imaging, and optical imaging of MXenes is presented. The challenges and future opportunities of applying MXene nanomaterials in the area of biomedicine are also discussed.

DNA is a perfect polymeric molecule for interfacing biology with material science to construct hydrogels that represent fascinating properties for a wide variety of biomedical applications. Tunable multifunctionality, convenient programmability, adequate biocompatibility, biodegradability, capability of precise molecular recognition, and high versatility have made DNA an irreplaceable building block for the construction of novel 3D hydrogels. DNA can be used as the only component of a hydrogel, the backbone or a cross‐linker that connects the main building blocks to form hybrid hydrogels through chemical reactions or physical entanglement. Responsive constructs of DNA with superior mechanical properties are very commonly reported nowadays, which can undergo macroscopic changes induced by various triggers, including alteration in ionic strength, temperature, and pH. These hydrogels can be prepared by various types of DNA building blocks, such as branched double‐stranded DNA, single‐stranded DNA, X‐shaped DNA, or Y‐shaped DNA through intermolecular i‐motif structures, DNA hybridization, enzyme ligation, or enzyme polymerization. These hydrogels are envisioned for a variety of applications, such as drug delivery, sensing, tissue engineering, 3D cell culture, and providing template for nanoparticle synthesis. This review highlights the design of ideal DNA hydrogels from biological and material points of view for future biomedical applications.

Diatomite is a natural porous silica material of sedimentary origin. Due to its peculiar properties, it can be considered as a valid surrogate of synthetic porous silica for nano-based drug delivery. In this work, we exploit the potential of diatomite nanoparticles (DNPs) for drug delivery with the aim of developing a successful dual-biofunctionalization method by polyethylene glycol (PEG) coverage and cell-penetrating peptide (CPP) bioconjugation, to improve the physicochemical and biological properties of the particles, to enhance the intracellular uptake in cancer cells, and to increase the biocompatibility of 3-aminopropyltriethoxysilane (APT) modified-DNPs. DNPs-APT-PEG-CPP showed hemocompatibility for up to 200 mu g mL(-1) after 48 h of incubation with erythrocytes, with a hemolysis value of only 1.3%. The cytotoxicity of the modified-DNPs with a concentration up to 200 mu g mL(-1) and incubation with MCF-7 and MDA-MB-231 breast cancer cells for 24 h, demonstrated that PEGylation and CPP-bioconjugation can strongly reduce the cytotoxicity of DNPs-APT. The cellular uptake of the modified-DNPs was also evaluated using the above mentioned cancer cell lines, showing that the CPP-bioconjugation can considerably increase the DNP cellular uptake. Moreover, the dual surface modification of DNPs improved both the loading of a poorly water-soluble anticancer drug, sorafenib, with a loading degree up to 22 wt%, and also enhanced the drug release profiles in aqueous solutions. Overall, this work demonstrates that the biofunctionalization of DNPs is a promising platform for drug delivery applications in cancer therapy as a result of its enhanced stability, biocompatibility, cellular uptake, and drug release profiles.

Diatomite is a natural fossil material of sedimentary origin, composed by fragments of diatom siliceous skeletons. Due to its chemical inertness, thermal stability, high surface area, non-toxicity and biocompatibility, diatomite is considered an ideal material for the preparation of diatomite silica drug delivery nanocarriers. In this work, the properties of diatomite nanoparticles (DNPs) as potential system for drug delivery in cancer cells were exploited.

The combination of chemo- and immunotherapy represents one promising strategy to overcome the existent challenges in the present-day anticancer therapy. Here, spermine-modified acetalated dextran nanoparticles (Sp-AcDEX NPs), co-loaded with the non-genotoxic molecule Nutlin-3a (Nut3a), and the cytokine granulocyte–macrophage colony-stimulating factor (GM-CSF), are developed to induce cancer cell death and create a specific antitumor immune response. These polymeric NPs release Nut3a in a pH dependent fashion and induce endosomal escape. Due to Nut3a, the loaded NPs exert specific toxicity toward wild-type p53 cancer cells while avoiding toxicity in immune cells. Furthermore, the NPs show intrinsic immune adjuvancy on monocyte derived-dendritic cells, upregulating the expression of cell surface CD83 and CD86 costimulatory markers. Finally, it is examined that by inducing MCF-7 breast cancer cell death and acting as immune adjuvants, the NPs can downregulate the expression of IL-10 and upregulate IL-1β, leading to proliferation of CD3+ and cytotoxic CD8+ T cells. Overall, the study suggests that Sp-AcDEX NPs loaded with Nut3a and GM-CSF is a promising system for chemo-immunotherapy, capable of inducing tumor cell death and stimulating immune response.

Active targeting of nanoparticles to receptor-overexpressing cancer cells has great potential for enhancing the cellular uptake of nanoparticles and for reducing fast clearance of the nanoparticles from the body. Herein, we present a preparation method of a porous silicon (PSi)-based nanodelivery system for breast cancer targeting, by covalently conjugating a synthesized amide-modified hyaluronic acid (HA(+)) derived polymer on the surface of undecylenic acid-modified thermally hydrocarbonized PSi (UnTHCPSi) nanoparticles. The resulting UnTHCPSi-HA(+) nanoparticles showed relatively small size, reduced polydispersibility, high biocompatibility, improved colloidal and human plasma stability, as well as enhanced cellular interactions and internalization. Moreover, we demonstrated that the enhanced cellular association of UnTHCPSi-HA(+) relies on the capability of the conjugated HA(+) to bind and consequently target CD44 receptors expressed on the surface of breast cancer cells, thus making the HA(+)-functionalized UnTHCPSi nanoparticles a suitable and promising nanoplatform for the targeting of CD44-overexpressing breast tumors and for drug delivery.

Advanced drug delivery technologies have emerged as an important focus of biomedical research. Despite the design and effectiveness of the technology, the nature of its interactions with surrounding tissues – their biocompatibility – is of utmost importance. Porous silicon (PSi) possesses unique physicochemical properties that are advantageous for biomedical applications. Despite the increase in the prevalence of engineered materials and the large number of studies found in the literature, little is still known about their safety and potential impact on human health. This chapter provides an overview of the aspects of biocompatibility and the assays used to assess the toxicity of PSi-based materials on cells ( in vitro ) and organs/tissues ( in vivo ). We summarize the continuing efforts for understanding the factors affecting biocompatibility of PSi-based materials. Several assessment techniques and methods are described and discussed herein.

Currently, developing a stable nanocarrier with high cellular internalization and low toxicity is a key bottleneck in nanomedicine. Here, we have developed a successful method to covalently conjugate poly(methyl vinyl ether-co-maleic acid) (PMVE-MA) copolymer on the surface of (3-aminopropyl)triethoxysilane-functionalized thermally carbonized porous silicon nanoparticles (APSTCPSi NPs), forming a surface negatively charged nanovehicle with unique properties. This polymer conjugated NPs could modify surface smoothness, charge, and hydrophilicity of the developed NPs, leading to considerable improvement in the colloidal and plasma stabilities via enhanced suspensibility and charge repulsion. Furthermore, despite the surface negative charge of the polymer-conjugated NPs, the cellular internalization was increased in both MDA-MB-231 and MCF-7 breast cancer cells. These results provide a proof-of-concept evidence that such polymer-based PSi nanocomposite can be extensively used as a promising candidate for intracellular drug delivery.

Targeted theranostic nanoparticles with dual pH and magnetic responsive properties for intracellular delivery are described by B. Herranz-Blanco, H. A. Santos, and co-workers on page 1904. Using a pH-switch nanoprecipitation method in organic-free solvents, a polymeric-drug conjugate solid nanoparticle containing encapsulated superparamagnetic iron oxide nanoparticles and decorated with a tumor homing peptide, iRGD, are targeted to endothelial and metastatic cancer cells.