Subnanometer-sized metal nanoclusters (NCs) with diameters <2 nm have emerged as promising materials in biomedical applications. Here, we report the synthesis of near-infrared (NIR)-emitting Au 14 nanoclusters using a small therapeutic molecule, D-penicillamine (DPA), as a surface stabilizing agent. We have characterized the morphology and composition of as-synthesized NCs using electron microscopy and mass spectrometry techniques. The photophysics of the NCs was investigated by UV−vis and photoluminescence (PL) spectroscopy. We found molecule-like features with three distinctive absorption bands at 390, 456, and 590 nm and a photoemission band at 696 nm. We observed that Au NCs specifically inhibited cancer cells dose-dependently through preferential uptake and imparted significant intracellular ROS. They did not show any acute toxicity in C57BL/6 mice at a dosage of 10 mg/kg, with predominant accumulation in the kidneys at the end of 24 h.
Graphitic carbon nitride (also known as g-CN or g-C3N4) has the intrinsic ability to generate electron–hole pairs under visible light illumination, resulting in the generation of reactive oxygen species (ROS). We report g-CN quantum dots (g-CNQDs) as a standalone photodynamic transducer for imparting significant oxidative stress in glioma cells, manifested by the loss of mitochondrial membrane potential. With an optimized treatment time, visible light source, and exposure window, the photodynamic treatment with g-CNQDs could achieve ∼90% cancer cell death via apoptosis. The g-CNQDs, otherwise biocompatible with normal cells up to 5 mg/mL, showed ∼20% necrotic cancer cell death in the absence of light due to membrane damage induced by a charge shielding effect at the acidic pH prevailing in the tumor environment. Acute toxicity analysis in C57BL/6 mice with intravenously injected g-CNQDs at a 20 mg/kg dose showed no signs of inflammatory response or organ damage.
Disintegrable inorganic nanoclusters (GIONs) with gold seed (GS) coating of an iron oxide core with a primary nanoparticle size less than 6 nm were prepared for theranostic applications. The GIONs possessed a broad near-infrared (NIR) absorbance at ∼750 nm because of plasmon coupling between closely positioned GSs on the iron oxide nanoclusters (ION) surface, in addition to the ∼513 nm peak corresponding to the isolated GS. The NIR laser-triggered photothermal response of GIONs was found to be concentration-dependent with a temperature rise of ∼8.5 and ∼4.5 °C from physiological temperature for 0.5 and 0.25 mg/mL, respectively. The nanoclusters were nonhemolytic and showed compatibility with human umbilical vein endothelial cells up to a concentration of 0.7 mg/mL under physiological conditions. The nanoclusters completely disintegrated at a lysosomal pH of 5.2 within 1 month. With an acute increase of over 400% intracellular reactive oxygen species soon after γ-irradiation and assistance from Fenton reaction-mediated supplemental oxidative stress, GION treatment in conjunction with radiation killed ∼50% of PLC/PRF/5 hepatoma cells. Confocal microscopy images of these cells showed significant cytoskeletal and nuclear damage from radiosensitization with GIONs. The cell viability further decreased to ∼10% when they were sequentially exposed to the NIR laser followed by γ-irradiation. The magnetic and optical properties of the nanoclusters enabled GIONs to possess a T 2 relaxivity of ∼223 mM −1 s −1 and a concentration-dependent strong photoacoustic signal toward magnetic resonance and optical imaging. GIONs did not incur any organ damage or evoke an acute inflammatory response in healthy C57BL/6 mice. Elemental analysis of various organs indicated differential clearance of gold and iron via both renal and hepatobiliary routes.
Hydrogels are a three-dimensional cross-linked network of hydrophilic polymers, extensively used for biomedical, biotechnological, and pharmaceutical applications. The functionality of hydrogels could be enhanced by synthesizing hydrogel nanocomposites that can both enable controlled release of drugs in a cancerous microenvironment and near-infrared-induced localized heat generation for combined chemo-photothermal therapy (chemo-PTT), a potent anticancer therapeutic approach. Herein, we developed a plasmonically active hydrogel with carboxymethyl chitosan (CMC) as the supporting matrix cross-linked with ZIF8 nanoparticles and Mg 2+ . The ZIF8 nanoparticles were loaded in situ with ultrasmall gold nanoparticles (UsGNPs) and an anticancer drug curcumin for localized chemo-PTT. The plasmonic hydrogel (PHG) showed viscoelastic and self-healing properties governed by the supramolecular interaction between ZIF8 and CMC. The injectable PHG exhibited a photothermal conversion efficiency of ∼41%. Chemo-PTT with Cur-PHG effectively inhibited 4T1 breast cancer under both in vitro and in vivo conditions. The biocompatible PHG was found to release UsGNPs from tumor tissues post intratumoral injection followed by predominant distribution in the liver and kidney. Due to the size of UsGNPs (<5 nm), they were consistently detected in urine over the period of treatment confirming the overall degradable nature of PHG that delivers a localized outcome with negligible systemic toxicity.
We report drug nanocrystals stabilized with host-specific serum proteins with high loading (∼63% w/w). The human serum derived curcumin nanoparticles (Cur-NanoSera) showed superior in vitro anticancer efficiency compared to a free drug with substantial hemocompatibility. The preadsorbed protein coating impeded further protein corona formation, even with repeated serum exposures. Acute and subacute toxicity evaluations post single and dual injections of C57BL/6 mice indicated that Cur-NanoSera showed no prominent inflammatory response or organ damage in the in-bred mice. Passive accumulation of Cur-NanoSera in tumor tissue significantly suppressed its growth in a syngeneic breast tumor model in addition to controlling tumor burden associated splenomegaly.
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