Cell Uptake Properties Research Articles

Rational design of pH-responsive nano-delivery system with improved biocompatibility and targeting ability from cellulose nanocrystals via surface polymerization for intracellular drug delivery

Cellulose nanocrystals (CNCs), derived from diverse sources and distinguished by their inherent biodegradability, excellent biocompatibility, and facile cellular engulfment due to their rod-like structure, hold great promise as carriers for the development of nano-delivery systems. In this work, highly efficient rod-like CNCs were employed as substrates for grafting glycidyl onto their surfaces through ring-opening polymerization, forming hyperbranched polymers with superior cell uptake properties. Subsequently, 4-vinylbenzeneboronic acid (VB) and poly (ethylene glycol) methyl ether methacrylate (PEGMA) were employed as monomers in the polymerization process to fabricate a pH-responsive targeted nano-delivery system, denoted as CNCs-VB-PEGMA, via single electron transfer reactive radical polymerization (SET-LRP) reaction. The CNCs-VB-PEGMA was successfully prepared and used for the loading of curcumin (Cur) to form a pH-responsive nano-delivery system (CNCs-VB-PEGMA-Cur), and the loading rate of Cur was as high as 70.0 %. Studies showed that this drug delivery system could actively targeting liver cancer cells with the 2D cells model and 3D tumor microsphere model, showing efficient liver cancer cell-killing ability. Collectively, the CNCs-VB-PEGMA drug delivery system has potential applications in liver cancer therapy as an actively targeting and pH-responsive drug delivery system.

Hollow Mesoporous SilicaNanoparticles for Dual Chemo-starvation Therapy of Hepatocellular Carcinoma.

This study aims at chemotherapy and starvation therapy of HCC via starvation and apoptosis. Hollow mesoporous organosilica nanoparticles (HMONs) with the thioether-hybrid structure were developed using an organic/inorganic co-templating assembly approach. Hydrofluoric acid was used to remove the internal MSN core for yielding large radial mesopores for loading drug cargos. The morphology and structure of NPs were determined using TEM and SEM. HMONs were stepwise surface modified with glucose oxidase (GOx), oxygen (O2) and Doxorubicin (DOX), and cancer cell membrane (CCM) for yielding CCM-coated HMONs (targeted stealth biorobots; TSBRs) for starvation, apoptotic, and enhanced cell uptake properties, respectively. The surface area and pore size distribution were determined via BET and BJH assays. The catalytic ability of GOx-modified NPs was measured using in vitro glucose conversion approach authenticated by H2O2 and pH determination assays. MTT assay was used to determine the cytotoxicities of NPs. Cell uptake and apoptotic assay were used for the NPs internalization and apoptosis mechanisms. The subcutaneous HepG2 tumor model was established in mice. The long-term in vivo toxicity was determined using blood assays. The prepared NPs were spherical, hollow and mesoporous with excellent surface area and pore size distribution. The GOx-modified NPs exhibited excellent catalytic activity. The TSBRs showed better cytotoxicity and reduce the tumor size and weight. The NPs showed long-term safety in vivo. TSBRs destroyed cancer cells by starvation and chemotherapy in both in-vitro and in-vivo settings which demonstrates its anti-cancer potential.

466 Development of a novel tocotrienol analogue, tocoflexol, as a radiomitigator

OBJECTIVES/GOALS: We have designed an analogue of the Vitamin E tocotrienols called tocoflexol, which improves their pharmacokinetic limitations to make it an effective radiation medical countermeasure. Our goal is to demonstrate that tocoflexol is an effective radiomitigator in vivo when administered after exposure to lethal doses of total body irradiation. METHODS/STUDY POPULATION: Tocoflexol was designed using computational techniques to improve binding to ATTP, the key transporter that reduces the rate of elimination of tocols. In vitro studies compared the antioxidant and cell uptake properties to conventional tocotrienols. Next, we used a mouse model of lethal total body irradiation to evaluate its radioprotection efficacy (treating before radiation). To determine the optimal administration route for radiomitigation (treating after radiation), we will test oral and subcutaneous dosing. Mouse survival will be monitored for 30 days after irradiation. Sample tissues will be taken to evaluate the ability of tocoflexol to protect key organs from acute radiation syndrome. The bioavailability of tocoflexol will be evaluated in a rodent model. RESULTS/ANTICIPATED RESULTS: Known Results: Results show that tocoflexol has potent antioxidant properties and high cell uptake. When tocoflexol was administered 24 hours before exposure to lethal doses of radiation, tocoflexol-treated mice showed 100% survival. Anticipated Results: Because of its improved bioavailability and pharmacokinetic properties, we expect that tocoflexol will show radiomitigation efficacy when administered 24 hours after radiation, improving survival and protecting key organ systems from acute radiation syndrome. DISCUSSION/SIGNIFICANCE: There is an unmet need for safe and effective radiomitigators that can offer multi-organ protection and be rapidly administered in the event of nuclear emergencies. Demonstration of radiomitigation efficacy will position tocoflexol as a prime candidate to be developed into a nuclear medical countermeasure and stockpiled for emergencies.

Maleimide constrained BAD BH3 domain peptides as BCL-xL Inhibitors: A versatile approach to rapidly identify sites compatible with peptide constraining

Development of protein–protein interaction (PPI) inhibitors remains a major challenge. A significant number of PPIs are mediated by helical recognition epitopes; although peptides derived from such epitopes are attractive templates for inhibitor design, they may not readily adopt a bioactive conformation, are susceptible to proteolysis and rarely elicit optimal cell uptake properties. Constraining peptides has therefore emerged as a useful method to mitigate against these liabilities in the development of PPI inhibitors. Building on our recently reported method for constraining peptides by reaction of dibromomaleimide derivatives with two cysteines positioned in an i and i + 4 relationship, in this study, we showcase the power of the method for rapid identification of ideal constraining positions using a maleimide-staple scan based on a 19-mer sequence derived from the BAD BH3 domain. We found that the maleimide constraint had little or a detrimental impact on helicity and potency in most sequences, but successfully identified i, i + 4 positions where the maleimide constraint was tolerated. Analyses using modelling and molecular dynamics (MD) simulations revealed that the inactive constrained peptides likely lose interactions with the protein as a result of introducing the constraint.

Self-Assembly Loading of Schisandra chinensis Nanoparticles and Its Effect on the Malignant Biological Behavior of Ovarian Cancer Cells

Schisandra polysaccharide (SCHP) was utilized as the target drug, and Zein (corn prolamine) was utilized as the drug carrier. First, SCHP/Zein nanoparticles (Zein-SCHP NPs) were prepared. Then, a polydopamine (PDP) coating was utilized to enhance the stability and tumor targeting of Zein. Finally, the folic acid (FA)-targeting ligand was covalently attached to the PDP-modified Zein-SCHP@PDP NP surface to form a highly pH-sensitive NP (Zein-SCHP@PDP-FA NPs) with active/passive targeting. In the experiment, apart from physical characterization of Zein-SCHP-based nanomaterials, the in vitro cytotoxicity and cell uptake properties of these materials were tested. In addition, an ovarian cancer cell line, SKOV3, was taken as the research object to explore the photodynamic-mediated killing effect of Zein-SCHP@PDP-FA NPs on this cancer cell. The results demonstrated that the average particle size of Zein-SCHP@PDP-FA NPs was (379.68±1.36) nm, the zeta potential was (−43.68±1.67) mV, the encapsulation efficiency was (97.86±1.38)%, and the drug loading was (11.75±0.16)%. Transmission electron microscope (TEM) suggested that the Zein-SCHP@PDP-FA NPs were spherical, and there was no adhesion between the particles. Differential scanning calorimetry (DSC) and far infrared (FIR) results indicated that SCHP existed in the NPs in the crystal structure and proved that the PDP and FA were successfully modified. The in vitro release of the drug showed that Zein-SCHP@PDP-FA NPs had sustained release, and the CCK-8 test showed that Zein-SCHP@PDP-FA NPs were highly cytotoxic and could notably reduce the IC50 values of SCHP. Furthermore, in vitro uptake experiments revealed that Zein-SCHP@PDP-FA NPs exhibited strong specific recognition in cells expressing different folate receptors. Compared with Zein-SCHP NPs and Zein-SCHP@PDP NPs, Zein-SCHP@PDP-FA NPs combined with photodynamic therapy enhanced reactive oxygen species (ROS) production in cells, downregulated hypoxia-inducible factor (HIF)-1α and interleukin (IL)-6 proteins, and exerted more destructive effects on SKOV3 cells.

Fitness Landscape-Guided Engineering of Locally Supercharged Virus-like Particles with Enhanced Cell Uptake Properties.

Protein-based nanoparticles are useful models for the study of self-assembly and attractive candidates for drug delivery. Virus-like particles (VLPs) are especially promising platforms for expanding the repertoire of therapeutics that can be delivered effectively as they can deliver many copies of a molecule per particle for each delivery event. However, their use is often limited due to poor uptake of VLPs into mammalian cells. In this study, we use the fitness landscape of the bacteriophage MS2 VLP as a guide to engineer capsid variants with positively charged surface residues to enhance their uptake into mammalian cells. By combining mutations with positive fitness scores that were likely to produce assembled capsids, we identified two key double mutants with internalization efficiencies as much as 67-fold higher than that of wtMS2. Internalization of these variants with positively charged surface residues depends on interactions with cell surface sulfated proteoglycans, and yet, they are biophysically similar to wtMS2 with low cytotoxicity and an overall negative charge. Additionally, the best-performing engineered MS2 capsids can deliver a potent anticancer small-molecule therapeutic with efficacy levels similar to antibody-drug conjugates. Through this work, we were able to establish fitness landscape-based engineering as a successful method for designing VLPs with improved cell penetration. These findings suggest that VLPs with positive surface charge could be useful in improving the delivery of small-molecule- and nucleic acid-based therapeutics.

Paclitaxel-based supramolecular hydrogel loaded with mifepristone for the inhibition of breast cancer metastasis.

Breast cancer is the leading cause of cancer death among women and almost all of the breast cancer‐caused mortality is related to metastasis. It has been reported that glucocorticoid facilitates the metastasis of breast cancer in mice, and mifepristone can antagonize the effect of glucocorticoid. Paclitaxel is one of the important drugs in the treatment of breast cancer. Mifepristone combined with paclitaxel could be an effective strategy for inhibiting breast cancer metastasis. However, their inherent defects, in terms of short blood circulation half‐life and lack of tumor targeting, not only limit their effectiveness but also cause adverse reactions. Therefore, our aim is to explore a novel protocol against breast cancer metastasis, further optimize its therapeutic efficacy by a nanodelivery system, and explore its mechanism. Herein, a paclitaxel‐conjugated and mifepristone‐loaded hydrogel (PM‐nano) was prepared by self‐assembly. Its characterizations were studied. The antimetastatic effect was evaluated in vitro and in vivo and its mechanism was also explored by western blot assay. The resultant PM‐nano was developed with favorable water solubility and good biocompatibility. Moreover, PM‐nano displayed increased cell uptake properties and stimulated drug release in the tumor micro‐acidic environment. The PM‐nano was more effective in inhibiting the proliferation and metastasis of breast cancer than other groups in vitro and in vivo. The PM‐nano might inhibit metastasis through glucocorticoid receptor/receptor tyrosine kinase‐like orphan receptor 1 and MMPs. Taken together, PM‐nano showed superior antimetastatic effects against breast cancer and excellent biocompatibility in vitro and in vivo, providing a new option for limiting metastasis.

Synthesis of KUE-siRNA Conjugates for Prostate Cancer Cell-Targeted Gene Silencing.

The delivery of siRNAs to selectively target cells poses a great challenge in RNAi-based cancer therapy. The lack of suitable cell-targeting methods seriously restricts the advance in delivering siRNAs to extrahepatic tissues. Based on prostate-specific membrane antigen (PSMA)-targeting ligands, we have synthesized a series of lysine-urea-glutamate (KUE)-siRNA conjugates and verified their effective cell uptake and gene silencing properties in prostate cancers. The results indicated that the KUE-siRNA conjugates could selectively enter PSMA+ LNCaP cells, eventually down-regulating STAT3 expression. Based on post-synthesis modification and receptor-mediated endocytosis, this strategy of constructing ligand-siRNA conjugates might provide a general method of siRNA delivery for cell-targeted gene silencing.

Interface Assembly to Magnetic Mesoporous Organosilica Microspheres with Tunable Surface Roughness as Advanced Catalyst Carriers and Adsorbents

Surface roughness endows microspheres with unique and useful features and properties like improved hydrophobicity, enhanced adhesion, improved stability at the oil-water interface, and superior cell uptake properties, thus expanding their applications. Core-shell magnetic mesoporous microspheres combine the advantages of magnetic particles and mesoporous materials and have exhibited wide applications in adsorption, catalysis, separation, and drug delivery. In this study, virus-like rough core-shell-shell-structured magnetic mesoporous organosilica (denoted as RMMOS) microspheres with controllable surface roughness were successfully obtained through electrostatic interaction-directed interface co-assembly. The obtained RMMOS microspheres possess uniform spherical morphology with tunable surface roughness, radially aligned pore channels with a diameter of 3.0 nm in the outer organosilica shell, high specific surface area (396 m2/g), large pore volume (0.66 cm3/g), high magnetization (35.1 emu/g), and superparamagnetic property. The RMMOS microspheres serve as desirable candidates to support Au nanoparticles (2.5 nm) and show superior catalytic activity and excellent stability in hydrogenation of 4-nitrophenol. In addition, the RMMOS microspheres modified with carboxylic groups further displayed promising performance in convenient adsorption removal of dyes in polluted water.

Nanoparticle delivery of a pH-sensitive prodrug of doxorubicin and a mitochondrial targeting VES-H8R8 synergistically kill multi-drug resistant breast cancer cells

Multi-drug resistance (MDR) remains a major obstacle in cancer treatment while being heavily dependent on mitochondrial activity and drug efflux. We previously demonstrated that cationic lipids, such as the vitamin E succinate modified octahistidine-octaarginine (VES-H8R8) conjugate, target mitochondria, resulting in depolarized mitochondria and inhibited drug efflux in MDR breast cancer cells. We hypothesized that the effective cell uptake, efflux inhibition, and mitochondrial depolarization properties of VES-H8R8 would synergistically enhance the toxicity of a pH-sensitive prodrug of doxorubicin (pDox) when co-encapsulated in nanoparticles (NPs). pDox was successfully synthesized and validated for pH-sensitive release from NPs under lysosome-mimicking, acidic conditions. The synergistic effect of VES-H8R8 and pDox was confirmed against MDR breast cancer cells in vitro. Importantly, synergism was only observed when VES-H8R8 and pDox were co-encapsulated in a single nanoparticulate system. The synergistic mechanism was investigated, confirming superior pDox uptake and retention, Pgp efflux inhibition, mitochondrial depolarization, and enhanced induction of ROS, and apoptosis. This work demonstrates the translational potential of doubly-loaded NPs co-encapsulating pDox with VES-H8R8 to synergistically kill MDR breast cancer cells.

CATIONIC NANOSTRUCTURED LIPID CARRIERS: OPTIMIZATION OF ZETA POTENTIAL AND EVALUATION

Objective: To fabricate, optimize and evaluate, Lipid-based cationic nanoparticulate dispersed system to improve the bio-adhesion property for ophthalmic use.
 Methods: Lipid-based cationic nanoparticulate dispersed system was fabricated by melt emulsification ultrasonication method and Box-Behnken design was utilized for optimization of formulation through the Design-Expert® program. The concentration of stabilizer, liquid lipid and Cetyltrimethylammonium Bromide (CTAB) was selected as variables (factors) while particle size, zeta potential and polydispersity index (PDI) were selected as a response for optimization purpose. Characterization of particle properties was performed using Transmission Electron Microscopy (TEM), Photon correlation spectroscopy (PCS). Fourier-transform infrared spectroscopy (FT-IR) was performed to study chemical interaction among ingredients. Rhodamine B entrapped CNLC formulation was used to study the interaction of NLC and CNLC on a three-dimensional and two-dimensional ocular tissue model for cell uptake and penetration properties.
 Results: Cationic nanostructured lipid carrier system was successfully fabricated by melt emulsification ultrasonication method. Characterization of nanoparticulate system using PCS revealed particle size in the range of 113.1 to 274.2 nm, PDI in a range of 0.147 to 0.280, while zeta potential in the range of 7.2 to 49.8 mV. The validation of statistical design suggested that it was suitable for navigation of design space. TEM imaging confirmed the results of PCS characterization. FT-IR study suggested a minimal chemical interaction among ingredients in CNLC. Confocal laser microscopic imaging for the interaction of NLC and CNLC on a three-dimensional and two-dimensional ocular tissue model revealed good penetration and bio-adhesion properties.
 Conclusion: The fabricated Cationic nanostructured lipid carrier system was found to be the potential ophthalmic novel drug delivery system with good bio-adhesion and penetration properties.

Azo-PROTAC: Novel Light-Controlled Small-Molecule Tool for Protein Knockdown.

Reversibly altering endogenous protein levels are persistent issues. Herein, we designed photoswitchable azobenzene-proteolysis targeting chimeras (Azo-PROTACs) by including azobenzene moieties between ligands for the E3 ligase and the protein of interest. Azo-PROTACs are light-controlled small-molecule tools for protein knockdown in cells. The light-induced configuration change can switch the active state to induce protein degradation activity, which can be reversely controlled by light exposure in intact cells. We compared the protein degradation abilities of Azo-PROTACs with different configurations and linker lengths. Using the stable form with the best degradation ability against the BCR-ABL fusion and ABL proteins in myelogenous leukemia K562 cells, we showed that Azo-PROTAC combines the potent protein knockdown and facile cell uptake properties of the small-molecule PROTAC with a reversible photoswitchability, offering a promising chemical knockdown strategy based on the light-induced reversible on/off properties.

The cell uptake properties and hyperthermia performance of Zn0.5Fe2.5O4/SiO2 nanoparticles as magnetic hyperthermia agents.

Zn0.5Fe2.5O4 nanoparticles (NPs) of 22 nm are synthesized by a one-pot approach and coated with silica for magnetic hyperthermia agents. The NPs exhibit superparamagnetic characteristics, high-specific absorption rate (SAR) (1083 wg−1, f = 430 kHz, H = 27 kAm−1), large saturation magnetization (Ms = 85 emu g−1), excellent colloidal stability and low cytotoxicity. The cell uptake properties have been investigated by Prussian blue staining, transmission electron microscopy and the inductively coupled plasma-mass spectrometer, which resulted in time-dependent and concentration-dependent internalization. The internalization appeared between 0.5 and 2 h, the NPs were mainly located in the lysosomes and kept in good dispersion after incubation with human osteosarcoma MG-63 cells. Then, the relationship between cell uptake and magnetic hyperthermia performance was studied. Our results show that the hyperthermia efficiency was related to the amount of internalized NPs in the tumour cells, which was dependent on the concentration and incubation time. Interestingly, the NPs could still induce tumour cells to apoptosis/necrosis when extracellular NPs were rinsed, but the cell kill efficiency was lower than that of any rinse group, which indicated that local temperature rise was the main factor that induced tumour cells to death. Our findings suggest that this high SAR and biocompatible silica-coated Zn0.5Fe2.O4 NPs could serve as new agents for magnetic hyperthermia.

Cellular Vesicles: New Insights in Engineering Methods, Interaction with Cells and Potential for Brain Targeting.

Cellular vesicles (CVs) have been proposed as alternatives to exosomes for targeted drug delivery. CVs, prepared from human embryonic kidney 293 cells (HEK-293), C57BL/6 mouse B16F10 skin melanoma cells (B16F10), and immortalized human cerebral microvascular endothelial cells (hCMEC/D3) by liposome technology methods, were characterized for morphology, cytotoxicity, and cell uptake properties. CV brain-targeting potential was evaluated in vitro on the hCMEC/D3 blood-brain barrier (BBB) model, and in vivo/ex vivo. CV sizes were between 135 and 285 nm, and the ζ-potential was negative. The dehydration-rehydration method conferred highest calcein loading and latency to CVs compared with other methods. The increased calcein leakage from CVs when compared with liposomes indicated their poor integrity, which was increased by pegylation. The in vivo results confirmed lower liver uptake by PEG-CVs (compared with nonpegylated) proving that the calcein integrity test is useful for prediction of CV biodistribution, as used for liposomes. The cell uptake of homologous origin CVs was not always higher compared with that of non-homologous. Nevertheless, CVs from hCMEC/D3 demonstrated the highest BBB permeability (in vitro) compared with OX-26 targeted liposomes, and brain localization (in vivo). CVs from hCMEC/D3 cells grown in different media demonstrated decreased interaction with brain cells and brain localization. Significant differences in proteome of the two latter CV types were identified by proteomics, suggesting a potential methodology for identification of organotropism-determining CV components.

A New Generation of Minor-Groove-Binding-Heterocyclic Diamidines That Recognize G·C Base Pairs in an AT Sequence Context.

We review the preparation of new compounds with good solution and cell uptake properties that can selectively recognize mixed A·T and G·C bp sequences of DNA. Our underlying aim is to show that these new compounds provide important new biotechnology reagents as well as a new class of therapeutic candidates with better properties and development potential than other currently available agents. In this review, entirely different ways to recognize mixed sequences of DNA by modifying AT selective heterocyclic cations are described. To selectively recognize a G·C base pair an H-bond acceptor must be incorporated with AT recognizing groups as with netropsin. We have used pyridine, azabenzimidazole and thiophene-N-methylbenzimidazole GC recognition units in modules crafted with both rational design and empirical optimization. These modules can selectively and strongly recognize a single G·C base pair in an AT sequence context. In some cases, a relatively simple change in substituents can convert a heterocyclic module from AT to GC recognition selectivity. Synthesis and DNA interaction results for initial example lead modules are described for single G·C base pair recognition compounds. The review concludes with a description of the initial efforts to prepare larger compounds to recognize sequences of DNA with more than one G·C base pairs. The challenges and initial successes are described along with future directions.

Development of a Potential Gallium-68-Labelled Radiotracer Based on DOTA-Curcumin for Colon-Rectal Carcinoma: From Synthesis to In Vivo Studies.

Colorectal cancer is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women worldwide. We have recently reported that curcuminoid complexes labelled with gallium-68 have demonstrated preferential uptake in HT29 colorectal cancer and K562 lymphoma cell lines compared to normal human lymphocytes. In the present study, we report a new gallium-68-labelled curcumin derivative (68Ga-DOTA-C21) and its initial validation as marker for early detection of colorectal cancer. The precursor and non-radioactive complexes were synthesized and deeply characterized by analytical methods then the curcuminoid was radiolabelled with gallium-68. The in vitro stability, cell uptake, internalization and efflux properties of the probe were studied in HT29 cells, and the in vivo targeting ability and biodistribution were investigated in mice bearing HT29 subcutaneous tumour model. 68Ga-DOTA-C21 exhibits decent stability (57 ± 3% after 120 min of incubation) in physiological media and a curcumin-mediated cellular accumulation in colorectal cancer cell line (121 ± 4 KBq of radiotracer per mg of protein within 60 min of incubation). In HT29 tumour-bearing mice, the tumour uptake of 68Ga-DOTA-C21 is 3.57 ± 0.3% of the injected dose per gram of tissue after 90 min post injection with a tumour to muscle ratio of 2.2 ± 0.2. High amount of activity (12.73 ± 1.9% ID/g) is recorded in blood and significant uptake of the radiotracer occurs in the intestine (13.56 ± 3.3% ID/g), lungs (8.42 ± 0.8% ID/g), liver (5.81 ± 0.5% ID/g) and heart (4.70 ± 0.4% ID/g). Further studies are needed to understand the mechanism of accumulation and clearance; however, 68Ga-DOTA-C21 provides a productive base-structure to develop further radiotracers for imaging of colorectal cancer.

Preparing a 68Ga-labeled Arginine Glycine Aspartate (RGD)-peptide for Angiogenesis.

The αvβ3 integrin is a heterodimeric adhesion molecule involved in tumor cell migration and angiogenesis. The integrin is overexpressed in angiogenic tumor endothelial cells, where it typically has a low concentration. This specific expression of αvβ3 makes it a valid biomarker for antiangiogenic and imaging drugs. As a functional imaging modality, positron emission tomography (PET) provides information about biochemical and physiological changes in vivo, due to its unique high sensitivity at the nanomolar scale. Hence, radiometal-based PET radiopharmaceuticals have received great attention for the non-invasive quantification of tumor angiogenesis. This paper provides a systemic protocol to prepare a new radiometal-labeled peptide for the evaluation of angiogenesis. This protocol contains information about radiochemical reliability, lipophilicity, cell uptake, serum stability, and pharmacokinetic properties. The 68Ga-RGD-peptide is one of the representative PET ligands toward αvβ3 integrin. Here, we introduce a protocol to prepare a 68Ga-RGD-peptide and the evaluation of its biological efficacy.

Tobacco Mosaic Virus-Functionalized Mesoporous Silica Nanoparticles, a Wool-Ball-like Nanostructure for Drug Delivery.

The design of versatile tools to improve cell targeting and drug delivery in medicine has become increasingly pertinent to nanobiotechnology. Biological and inorganic nanocarrier drug delivery systems are being explored, showing advantages and disadvantages in terms of cell targeting and specificity, cell internalization, efficient payload delivery, and safety profiles. Combining the properties of a biological coating on top of an inorganic nanocarrier, we hypothesize that this hybrid system would improve nanoparticle-cell interactions, resulting in enhanced cell targeting and uptake properties compared to the bare inorganic nanocarrier. Toward this goal, we engineered a hierarchical assembly featuring the functionalization of cargo-loaded mesoporous silica nanoparticles (MSNPs) with tobacco mosaic virus (TMV) as a biological coating. The MSNP functions as a delivery system because the porous structure enables high therapeutic payload capacity, and TMV serves as a biocompatible coating to enhance cell interactions. The resulting MSNP@TMV nanohybrids have a wool-ball-like appearance and demonstrate enhanced cell uptake, hence cargo delivery properties. The MSNP@TMV have potential for medical applications such as drug delivery, contrast agent imaging, and immunotherapy.

Mixed-charge pseudo-zwitterionic mesoporous silica nanoparticles with low-fouling and reduced cell uptake properties

The design of drug delivery systems needs to consider biocompatibility and host body recognition for an adequate actuation. In this work, mesoporous silica nanoparticles (MSNs) surfaces were successfully modified with two silane molecules to provide mixed-charge brushes (-NH3⊕/-PO3⊝) and well evaluated in terms of surface properties, low-fouling capability and cell uptake in comparison to PEGylated MSNs. The modification process consists in the simultaneous direct-grafting of hydrolysable short chain amino (aminopropyl silanetriol, APST) and phosphonate-based (trihydroxy-silyl-propyl-methyl-phosphonate, THSPMP) silane molecules able to provide a pseudo-zwitterionic nature under physiological pH conditions. Results confirmed that both mixed-charge pseudo-zwitterionic MSNs (ZMSN) and PEG-MSN display a significant reduction of serum protein adhesion and macrophages uptake with respect to pristine MSNs. In the case of ZMSNs, this reduction is up to a 70–90% for protein adsorption and c.a. 60% for cellular uptake. This pseudo-zwitterionic modification has been focused on the aim of local treatment of bacterial infections through the synergistic effect between the inherent antimicrobial effect of mixed-charge system and the levofloxacin antibiotic release profile. These findings open promising future expectations for the effective treatment of bacterial infections through the use of mixed-charge pseudo-zwitterionic MSNs furtive to macrophages and with antimicrobial properties. Statement of SignificanceHerein a novel antimicrobial mixed-charge pseudo-zwitterionic MSNs based system with low-fouling and reduced cell uptake behavior has been developed. This chemical modification has been performed by the simultaneous grafting of short chain organosilanes, containing amino and phosphonate groups, respectively. This nanocarrier has been tested for local infection treatment through the synergy between the antimicrobial effect of mixed-charge brushes and the levofloxacin antibiotic release profile.

Reaching Biocompatibility with Nanoclays: Eliminating the Cytotoxicity of Ir(III) Complexes.

Cyclometalated IrIII complexes are promising candidates for biomedical applications but high cytotoxicity limits their use as imaging and sensing agents. We herein introduce the use of Laponite as carrier for triplet-emitting cyclometalated IrIII complexes. Laponite is a versatile nanoplatform because of its biocompatibility, dispersion stability and large surface area that readily adsorbs functional nonpolar and cationic molecules. These inorganic-organic hybrid nanomaterials mask cytotoxicity, show efficient cell uptake and increase luminescent properties and photostability. By camouflaging intrinsic cytotoxicity, this simple method potentially extends the palette of available imaging and sensing dyes to any metal-organic complexes, especially those that are usually cytotoxic.