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High-contrast optical imaging is achievable using phosphorescent labels to suppress the short-lived background due to the optical backscatter and autofluorescence. However, the long-lived phosphorescence is generally incompatible with high-speed laser-scanning imaging modalities. Here, we show that upconversion nanoparticles of structure NaYF 4 :Yb co-doped with 8% Tm (8T-UCNP) in combination with a commercial laser-scanning multiphoton microscopy are uniquely suited for labeling biological systems to acquire high-resolution images with the enhanced contrast. In comparison with many phosphorescent labels, the 8T-UCNP emission lifetime of ∼ 15 µs affords rapid image acquisition. The high-order optical nonlinearity of the 8T-UCNP ( n ≈ 4, as confirmed experimentally and theoretically) afforded pushing the resolution limit attainable with UCNPs to the diffraction-limit. The contrast enhancement was achieved by suppressing the background using (i) bandpass spectral filtering of the narrow emission peak of 8T-UCNP at 455-nm, and (ii) time-gating implemented with a time-correlated single-photon counting system that demonstrated the contrast enhancement of > 2.5-fold of polyethyleneimine-coated 8T-UCNPs taken up by human breast adenocarcinoma cells SK-BR-3. As a result, discrete 8T-UCNP nanoparticles became clearly observable in the freshly excised spleen tissue of laboratory mice 15-min post intravenous injection of an 8T-UCNP solution. The demonstrated approach paves the way for high-contrast, high-resolution, and high-speed multiphoton microscopy in challenging environments of intense autofluorescence, exogenous staining, and turbidity, as typically occur in intravital imaging.

Zinc oxide nanoparticle (ZnO NP)-based sunscreens are generally considered safe because the ZnO NPs do not penetrate through the outermost layer of the skin, the stratum corneum (SC). However, cytotoxicity of zinc ions in the viable epidermis (VE) after dissolution from ZnO NP and penetration into the VE is ill-defined. We therefore quantified the relative concentrations of endogenous and exogenous Zn using a rare stable zinc-67 isotope (67Zn) ZnO NP sunscreen applied to excised human skin and the cytotoxicity of human keratinocytes (HaCaT) using multiphoton microscopy, zinc-selective fluorescent sensing, and a laser-ablation inductively coupled plasma–mass spectrometry (LA-ICP-MS) methodology. Multiphoton microscopy with second harmonic generation imaging showed that 67ZnO NPs were retained on the surface or within the superficial layers of the SC. Zn fluorescence sensing revealed higher levels of labile and intracellular zinc in both the SC and VE relative to untreated skin, confirming that dissolved zinc species permeated across the SC into the VE as ionic Zn and significantly not as ZnO NPs. Importantly, the LA-ICP-MS estimated exogenous 67Zn concentrations in the VE of 1.0 ± 0.3 μg/mL are much lower than that estimated for endogenous VE zinc of 4.3 ± 0.7 μg/mL. Furthermore, their combined total zinc concentrations in the VE are much lower than the exogenous zinc concentration of 21 to 31 μg/mL causing VE cytotoxicity, as defined by the half-maximal inhibitory concentration of exogenous 67Zn found in human keratinocytes (HaCaT). This speaks strongly for the safety of ZnO NP sunscreens applied to intact human skin and the associated recent US FDA guidance.

Colonization of distant organs by tumor cells is a critical step of cancer progression. The initial avascular stage of this process (micrometastasis) remains almost inaccessible to study due to the lack of relevant experimental approaches. Herein, we introduce an in vitro/in vivo model of organ-specific micrometastases of triple-negative breast cancer (TNBC) that is fully implemented in a cost-efficient chick embryo (CE) experimental platform. The model was built as three-dimensional (3D) tissue engineering constructs (TECs) combining human MDA-MB-231 cells and decellularized CE organ-specific scaffolds. TNBC cells colonized CE organ-specific scaffolds in 2–3 weeks, forming tissue-like structures. The feasibility of this methodology for basic cancer research, drug development, and nanomedicine was demonstrated on a model of hepatic micrometastasis of TNBC. We revealed that MDA-MB-231 differentially colonize parenchymal and stromal compartments of the liver-specific extracellular matrix (LS-ECM) and become more resistant to the treatment with molecular doxorubicin (Dox) and Dox-loaded mesoporous silica nanoparticles than in monolayer cultures. When grafted on CE chorioallantoic membrane, LS-ECM-based TECs induced angiogenic switch. These findings may have important implications for the diagnosis and treatment of TNBC. The methodology established here is scalable and adaptable for pharmacological testing and cancer biology research of various metastatic and primary tumors.

Applications of nanoparticles (NPs) in the life sciences require control over their properties in protein-rich biological fluids, as an NP quickly acquires a layer of proteins on the surface, forming the so-called “protein corona” (PC). Understanding the composition and kinetics of the PC at the molecular level is of considerable importance for controlling NP interaction with cells. Here, we present a systematic study of hard PC formation on the surface of upconversion nanoparticles (UCNPs) coated with positively-charged polyethyleneimine (PEI) and negatively-charged poly (acrylic acid) (PAA) polymers in serum-supplemented cell culture medium. The rationale behind the choice of UCNP is two-fold: UCNP represents a convenient model of NP with a size ranging from 5 nm to >200 nm, while the unique photoluminescent properties of UCNP enable direct observation of the PC formation, which may provide new insight into this complex process. The non-linear optical properties of UCNP were utilised for direct observation of PC formation by means of fluorescence correlation spectroscopy. Our findings indicated that the charge of the surface polymer coating was the key factor for the formation of PC on UCNPs, with an ensuing effect on the NP–cell interactions.

Gold nanorods (AuNRs) have attracted high attention because of their multifunctions and potential applications in optical, electronic, catalytic and biomedical areas. This study demonstrates a key role of silver (Ag) atoms/clusters, experimentally and theoretically, in the formation and growth of AuNRs. It was found that the addition of silver salt (silver nitrate) can preferably deposit on certain Au crystalline {100} and/or {110} facets to affect the stacking of Au atoms when form and grow to AuNRs in the reported reaction system, resulting in slower atomic stacking on these two {100} and {110} facets but regular growth on the {111} facets. If no use of silver salt(s), gold nanospheres rather than nanorods were obtained in such a reaction system. It was found, by theoretical simulations (molecular dynamic method, MD), that Ag atoms can be oxidized to Ag + ions by AuCl 4 − ions and exist in a short lifetime, which finally diffuses out from the Au crystal structure. The findings would be useful for better understanding the role of Ag in the formation and growth of AuNRs with crystal facet control, which will be beneficial for catalytic and gas sensing applications that often require highly exposed crystalline facets. Graphical abstract Silver-assisted synthesis of gold nanorods in the presence of CTAB in aqueous solution has been confirmed by both experimental method and molecular dynamic simulations.

Bladder cancer is the ninth most common cancer worldwide. Due to a high risk of recurrence and progression of bladder cancer, every patient needs long-term surveillance, which includes regular cystoscopy, sometimes followed by a biopsy of suspicious lesions or resections of recurring tumours. This study addresses the development of novel biohybrid nanocomplexes representing upconversion nanoparticles (UCNP) coupled to antibodies for photoluminescent (PL) detection of bladder cancer cells. Carrying specific antibodies, these nanoconjugates selectively bind to urothelial carcinoma cells and make them visible by emitting visible PL upon excitation with deeply penetrating near-infrared light. UCNP were coated with a silica layer and linked to anti-Glypican-1 antibody MIL38 via silica-specific solid-binding peptide. Conjugates have been shown to specifically attach to urothelial carcinoma cells with high expression of Glypican-1. This result highlights the potential of produced conjugates and conjugation technology for further studies of their application in the tumour detection and fluorescence-guided resection.

In the natural fluidic environment of a biological system, nanoparticles swiftly adsorb plasma proteins on their surface forming a “protein corona”, which profoundly and often adversely affects their residence in the systemic circulation in vivo and their interaction with cells in vitro. It has been recognized that preformation of a protein corona under controlled conditions ameliorates the protein corona effects, including colloidal stability in serum solutions. We report on the investigation of the stabilizing effects of a denatured bovine serum albumin (dBSA) protein corona formed on the surface of upconversion nanoparticles (UCNPs). UCNPs were chosen as a nanoparticle model due to their unique photoluminescent properties suitable for background-free biological imaging and sensing. UCNP surface was modified with nitrosonium tetrafluoroborate (NOBF4) to render it hydrophilic. UCNP-NOBF4 nanoparticles were incubated in dBSA solution to form a dBSA corona followed up by lyophilization. As produced dBSA-UCNP-NOBF4 demonstrated high photoluminescence brightness, sustained colloidal stability after long-term storage and the reduced level of serum protein surface adsorption. These results show promise of dBSA-based nanoparticle pretreatment to improve the amiability to biological environments towards theranostic applications.

Early stages of colonization of distant organs by metastatic cancer cells (micrometastasis) remain almost inaccessible to study due to lack of relevant experimental approaches. Here, we show the first 3D tissue engineered model of hepatic micrometastasis of triple negative breast cancer (TNBC). It reproduces characteristic histopathological features of the disease and reveals that metastatic TNBC cells colonize liver parenchymal and stromal extracellular matrix with different speed and by different strategies. These engineered tumors induce the angiogenic switch when grafted in vivo, confirming their metastatic-specific behaviour. Furthermore, we proved feasibility and biological relevance of our model for drug and nanoparticle testing and found a down-regulatory effect of the liver microenvironment of the sensitivity of TNBC cells to chemotherapeutic drug doxorubicin in free and nanoformulated forms. The convenient and affordable methodology established here can be translated to other types of metastatic tumors for basic cancer biology research and adapted for high-throughput assays.