In biological environments, nanomaterials associate with proteins forming a protein corona (PC). The PC may alter the nanomaterial’s pharmacokinetics and pharmacodynamics, thereby influencing toxicity. Using a label-free mass spectrometry-based proteomics approach, the composition of the PC is examined for a set of nanotubes (NTs) including unmodified and carboxylated single- (SWCNT) and multi-walled carbon nanotubes (MWCNT), polyvinylpyrrolidone (PVP)-coated MWCNT (MWCNT-PVP), and nanoclay. NTs are incubated for 1 h in simulated cell culture conditions, then washed, resuspended in PBS, and assessed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) for their associated PC. To determine those attributes that influence PC formation, the NTs are extensively characterized. NTs had negative zeta potentials in water (SWCNT-COOH < MWCNT-COOH < unmodified NTs) while carboxylation increases their hydrodynamic sizes. All NTs are also found to associate a common subset of proteins including albumin, titin, and apolipoproteins. SWCNT-COOH and MWCNT-COOH are found to bind the greatest number of proteins (181 and 133 respectively) compared to unmodified NTs (< 100), suggesting covalent binding to protein amines. Modified NTs bind a number of unique proteins compared to unmodified NTs, implying hydrogen bonding and electrostatic interactions are involved in PC formation. PVP-coating of MWCNT did not influence PC composition, further reinforcing the possibility of hydrogen bonding and electrostatic interactions. No relationships are found between PC composition and corresponding isoelectric point, hydropathy, or aliphatic index, implying minimal roles of hydrophobic interaction and pi-stacking.
The characterization of nanomaterials and their influence and interactions on the biology of cells and tissues are still partially unknown. Multistage nanovectors based on mesoporous silicon have been extensively studied for drug delivery, thermal heating and improved diagnostic imaging. Here we analyzed the short and long-term changes occurring in human cells upon the internalization of mesoporous silicon nanovectors (MSV). Using qualitative and quantitative techniques as well as in vitro and in vivo biochemical, cellular and functional assays, we demonstrated that MSV did not cause any significant acute or chronic effects on cells and tissues. We analyzed in vitro cell toxicity and viability, the maintenance of cell phase cycling, and the architecture upon the internalization of MSV. In addition, we evaluated if MSV produced any pro-inflammatory response and studied its biocompatibility in vivo. We followed the biodistribution of MSV using longitudinal in vivo imaging and assessed organ accumulation using quantitative elemental and fluorescent techniques. Finally, a thorough pathological analysis of collected tissues demonstrated a mild transient systemic response in the liver that dissipated upon clearance of particles. In conclusion, with this study we propose that future endeavors aimed at understanding the toxicology of naked drug carriers should be designed to address their impact using in vitro and in vivo short and long-term evaluations of systemic response.
Mesoporous silica nanospheres (MSNs) are a promising material for magnetic resonance imaging (MRI) contrast agents. In this paper multifunctional MSNs with cleavable Gd(III) chelates are synthesized and characterized, and their applicability as MRI contrast agents is demonstrated both in vitro and in vivo. The MSNs contain Gd(III) chelates that are covalently linked via a redox-responsive disulfide moiety. The MSNs are further functionalized with polyethylene glycol (PEG) and an anisamide ligand to improve their biocompatibility and target specificity. The effectiveness of MSNs as an MRI imaging contrast agent and their targeting ability are successfully demonstrated in vitro using human colon adenocarcinoma and pancreatic cancer cells. Finally, the capability of this platform as an in vivo MRI contrast agent is tested using a 3T scanner. The Gd(III) chelate was quickly cleaved by the blood pool thiols and eliminated through the renal excretion pathway. Further tuning of the Gd(III) chelate release kinetics is needed before the MSN system can be used as target-specific MRI contrast agents in vivo.
Nanocarriers are a new type of nonviral gene carriers, many of which have demonstrated a broad range of pharmacological and biological properties, such as being biodegradable in the body, stimulus-responsive towards the surrounding environment, and an abiltiy to specifically targeting certain disease sites. By summarizing some main types of nanocarriers, this Concept considers the current status and possible future directions of the potential clinical applications of multifunctional nanocarriers, with primary attention on the combination of such properties as biodegradability, targetability, transfection ability, and stimuli sensitivity.
A class of core-shell nanoparticles possessing a layer of biocompatible shell and hydrophobic core with embedded oxygen-sensitive platinum-porphyrin (PtTFPP) dyes is developed via a radical-initiated microemulsion co-polymerization strategy. The influences of host matrices and the PtTFPP incorporation manner on the photophysical properties and the oxygen-sensing performance of the nanoparticles are investigated. Self-loading capability with cells and intracellular-oxygen-sensing ability of the as-prepared nanoparticle probes in the range 0%-20% oxygen concentration are confirmed. Polymeric nanoparticles with optimized formats are characterized by their relatively small diameter (<50 nm), core-shell structures with biocompatible shells, covalent-attachment-imparted leak-free construction, improved lifetime dynamic range (up to 44 s), excellent storage stability and photostability, and facile cell uptake. The nanoparticles' small sensor diameter and core-shell structure with biocompatible shell make them suitable for intracellular detection applications. For intracellular detection applications, the leak-free feature of the as-prepared nanoparticle sensor effectively minimizes potential chemical interferences and cytotoxicity. As a salient feature, improved lifetime dynamic range of the sensor is expected to enable precise oxygen detection and control in specific practical applications in stem-cell biology and medical research. Such a feature-packed nanoparticle oxygen sensor may find applications in precise oxygen-level mapping of living cells and tissue.
A novel light-operated vehicle for targeted intracellular drug delivery is constructed using photosensitizer-incorporated G-quadruplex DNA-capped mesoporous silica nanoparticles. Upon light irradiation, the photosensitizer generates ROS, causing the DNA capping to be cleaved and allowing cargo to be released. Importantly, this platform makes it possible to develop a drug-carrier system for the synergistic combination of chemotherapy and PDT for cancer treatment with spatial/temporal control. Furthermore, the introducing of targeting ligands further improves tumor targeting efficiency. The excellent biocompatibility, cell-specific intracellular drug delivery, and cellular uptake properties set up the basis for future biomedical application that require in vivo controlled, targeted drug delivery.
Amyloid fibril formation is a critical step in Alzheimer's disease (AD) pathogenesis. Inhibition of A aggregation has shown promising against AD and has been used in clinic trials. Here, a novel strategy is reported for the self-assembly of polyoxometalate-peptide (POM@P) hybrid particles as bifunctional A inhibitors. The two-in-one bifunctional POM@P nanoparticles show an enhanced inhibition effect on amyloid aggregation in mice cerebrospinal fluid. Incorporating a clinically used A fibril-staining dye, congo red (CR), into the hybrid colloidal spheres, the nanoparticles can also act as an effective fluorescent probe to monitor the inhibition process of POM@P via CR fluorescence change in real time. It is believed that such flexible organic-inorganic hybrid systems may prompt the design of new multifunctional materials for AD treatment.
Multifunctional lanthanide-doped porous nanoparticles are prepared via a facile one-step solvothermal route by employing aptamers as the biotemplate. The nanoparticles feature excellent aqueous dispersibility and biospecific properties and could work as effective nanoprobes for targeted imaging and drug delivery. With aptamer being in principle available for any kind of target, this synthetic strategy may open the door to a new generation of nanoprobes for bioapplications such as time-resolved biodetection, multimode bioimaging/biolabeling, and targeted cancer therapy.
Incorporating the agents for magnetic resonance imaging (MRI), optical imaging, and therapy in one nanostructured matrix to construct multifunctional nanomedical platform has attracted great attention for simultaneous diagnostic and therapeutic applications. In this work, a facile methodology is developed to construct a multifunctional anticancer drug nanocarrier by combining the special advantages of upconversion nanoparticles and mesoporous silica. -NaYF4:Yb3+, Er3+@-NaGdF4:Yb3+ is chosen as it can provide the dual modality of upconversion luminescence and MRI. Then mesoporous silica is directly coated onto the upconversion nanoparticles to form discrete, monodisperse, highly uniform, and core-shell structured nanospheres (labeled as UCNPs@mSiO(2)), which are subsequently functionalized with hydrophilic polymer poly(ethylene glycol) (PEG) to improve the colloidal stability and biocompatibility. The obtained multifunctional nanocomposites can be used as an anticancer drug delivery carrier and applied for imaging. The anticancer drug doxorubicin (DOX) is absorbed into UCNPs@mSiO(2)-PEG nanospheres and released in a pH-sensitive pattern. In vitro cell cytotoxicity tests on cancer cells verify that the DOX-loaded UCNPs@mSiO(2)-PEG has comparable cytotoxicity with free DOX at the same concentration of DOX. In addition, the T-1-weighted MRI that measures in aqueous solutions reveals that the contrast brightening increases with the concentration of Gd3+ component. Upconversion luminescence images of UCNPs@mSiO(2)-PEG uptaken by cells show green emission under 980 nm infrared laser excitation. Finally, the nanocomposites show low systematic toxicity and high in vivo antitumor therapy efficacy. These findings highlight the fascinating features of upconversion-mesoporous nanocomposites as multimodality imaging contrast agents and nanocarrier for drug molecules.