An injectable and self-healing collagen-gold hybrid hydrogel is spontaneously formed by electrostatic self-assembly and subsequent biomineralization. It is demonstrated that such collagen-based hydrogels may be used as an injectable material for local delivery of therapeutic agents, showing enhanced antitumor efficacy.
The design of cancer-targeting particles with precisely-tuned physiocochemical properties may enhance delivery of therapeutics and access to pharmacological targets. However, molecular level understanding of the interactions driving the fate of nanomedicine in biological systems remains elusive. Here, we show that ultrasmall (< 10 nm in diameter) poly(ethylene glycol) (PEG)-coated silica nanoparticles, functionalized with melanoma-targeting peptides, can induce a form of programmed cell death known as ferroptosis in starved cancer cells and cancer-bearing mice. Tumor xenografts in mice intravenously injected with nanoparticles using a high-dose multiple injection scheme exhibit reduced growth or regression, in a manner that is reversed by the pharmacological inhibitor of ferroptosis, liproxstatin-1. These data demonstrate that ferroptosis can be targeted by ultrasmall silica nanoparticles and may have therapeutic potential.
Ultrasmall fluorescent silica nanoparticles (SNPs) and core−shell SNPs surface functionalized with polyethylene glycol (PEG), specific surface ligands, and overall SNP size in the regime below 10 nm are of rapidly increasing interest for clinical applications, because of their favorable biodistribution and safety profiles. Here, we present an aqueous synthesis methodology for the preparation of narrowly size-dispersed SNPs and core−shell SNPs with size control below 1 nm, i.e., at the level of a single atomic layer. Different types of fluorophores, including near-infrared (NIR) emitters, can be covalently encapsulated. Brightness can be enhanced via addition of extra silica shells. This methodology further enables synthesis of <10 nm sized fluorescent core and core−shell SNPs with previously unknown compositions. In particular, the addition of an aluminum sol gel precursor leads to fluorescent aluminosilicate nanoparticles (ASNPs) and core−shell ASNPs. Encapsulation efficiency and brightness of highly negatively charged NIR fluorophores is enhanced, relative to the corresponding SNPs without aluminum. Resulting particles show quantum yields of ∼0.8, i.e., starting to approach the theoretical brightness limit. All particles can be PEGylated providing steric stability. Finally, heterobifunctional PEGs can be employed to introduce ligands onto the PEGylated particle surface of fluorescent SNPs, core−shell SNPS, and their aluminum-containing analogues, producing ligand-functionalized <10 nm NIR fluorescent nanoprobes. In order to distinguish these water-based-synthesis-derived materials from the earlier alcohol-based modified Stober process derived fluorescent core−shell SNPs referred to as Cornell dots or C dots, the SNPs and ASNPs described here and synthesized in water will be referred to as Cornell prime dots or C′ dots and AlC′ dots. These organic−inorganic hybrid nanomaterials may find applications in nanomedicine, including cancer diagnostics and therapy (theranostics).
There are tremendous challenges from both tumor and its therapeutic formulations affecting the effective treatment of tumor, including tumor recurrence, and complex multistep preparations of formulation. To address these issues, herein a simple and green approach based on the self-assembly of therapeutic agents including a photosensitizer (chlorine e6, Ce6) and a chemotherapeutic agent (doxorubicin, DOX) was developed to prepare carrier-free nanoparticles (NPs) with the ability to inhibit tumor recurrence. The designed NPs were formed by self-assembly of Ce6 and DOX associated with electrostatic, π-π stacking and hydrophobic interactions. They have a relatively uniform size of average 70 nm, surface charge of -20 mV and high drug encapsulation efficiency, which benefits the favorable accumulation of drugs at the tumor region through a potential enhanced permeability and retention (EPR) effect as compared to their counterpart of free Ce6 solution. In addition, they could eradiate tumors without recurrence in a synergistic way following one treatment cycle. Furthermore, the NPs are safe without any activation of inflammation or immune response in separated organs. Taken together, the rationale of these pure nanodrugs via the self-assembly approach might open an alternative avenue and give inspiration to fabricate new carrier-free nanodrugs for tumor theranostics, especially for two small molecular antitumor drugs with the aim of combinational antitumor therapy in a synergistic way.
Surface modification with polyethylene glycol (PEG; PEGylation) is a widely used technique to improve nanoparticle (NP) stability, biocompatibility, and biodistribution profiles. In particular, PEGylation of silica surfaces and coatings plays a pivotal role across various classes of NPs. Despite the use of numerous protocols there is limited fundamental understanding of the mechanisms of these processes for NPs. Here, after reaction optimization for particle stability, we employ fluorescence correlation and crosscorrelation spectroscopy (FCS, FCCS) on ultrasmall (<10 nm) fluorescent silica nanoparticles (SNPs) in water as a test bed. We show unexpected fast reaction kinetics in successful PEGylation observed even at nanomolar concentrations and attributed this to instant noncovalent adsorption of PEG molecules to the SNP surface preceding covalent attachment. Further studies of various reaction conditions enable the elucidation of process design criteria for NP PEGylation and surface modification with functional ligands, which may be applicable to a broad range of NPs thereby accelerating progress in fields ranging from biosensing to nanomedicine.
The M1 protein of influenza virus is thought to make contact with the cytoplasmic tails of the glycoprotein spikes, lipid molecules in the viral membrane, and the internal ribonucleoprotein particles. Here we show electron micrographs of negatively stained virus particles in which M1 is visualized as a 60-A-long rod that touches the membrane but apparently is not membrane inserted. Photolabeling with a membrane restricted reagent resulted in labeling of the transmembrane region of haemagglutinin but not of M1, also suggesting that most of M1 is not embedded into the hydrophobic core of the viral membrane. Finally, in vitro reconstitution experiments using soluble M1 protein and synthetic liposomes or Madin-Darby canine kidney cell membranes suggest that M1 can bind to negatively charged liposomes and to the cellular membranes and that this binding can be prevented under high-salt conditions. Although none of these experiments prove that there does not exist a minor fraction of M1 that is membrane inserted, it appears that most of M1 in the virus is membrane associated through electrostatic interactions.
Ultrasmall sub-10 nm nanoprobes and carriers are of significant interest due to their favorable biodistribution characteristics in in vivo experiments. Here we describe the one-pot synthesis of PEGylated mesoporous silica nanoparticles with a single pore, tunable sizes around 9 nm and narrow size distributions that can be labeled with near-infrared dye Cy5.5. Particles are characterized by a combination of transmission electron microscopy, dynamic light scattering, fluorescence correlation spectroscopy, optical spectroscopy, nuclear magnetic resonance spectroscopy, and nitrogen sorption/desorption measurements. The possibility to distinguish an "inside" and "outside" may render these particles an interesting subject for further studies in sensing, drug delivery, and theranostics applications.
Biocatalysis is promising for sustainable production of polymers. Enzyme-initiated reversible addition− fragmentation chain transfer (RAFT) polymerization is reported. Horseradish peroxidase (HRP) catalyzes oxidation of acetylacetone (ACAC) by hydrogen peroxide to generate ACAC radicals, which in the presence of a suitable chain transfer agent initiate efficient and well-controlled RAFT polymerization in aqueous buffer solution at room temperature. The versatility of HRP-initiated RAFT polymerization was demonstrated by controlled polymerization of a wide range of monomers, including both more and less activated monomers, under a variety of conditions, including both homogeneous solution polymerization and heterogeneous dispersion polymerization conditions. In all cases, the polymerization afforded excellent pseudo-first-order kinetics, predictable molecular weights, and narrow molecular weight distributions. Operation via RAFT mechanism of this HRP-initiated polymerization was confirmed by a combination of MALDI-ToF, NMR, and UV−vis as well as by chain extension to make well-defined block copolymers. The mildness, specificity, and biocompatibility of HRP-initiated RAFT polymerization were illustrated by controlled polymerization in undiluted fetal bovine serum (FBS) solution. RAFT polymerization initiated by glucose oxidase (GOx)−HRP enzymatic cascade catalysis was developed, opening up a new avenue to potential green synthesis of precision polymers by controlled radical polymerization in air.
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