Improving the effectiveness of cancer therapy will require tools that enable more specific cancer targeting and improved tumor visualization. Theranostics have the potential for improving cancer care because of their ability to serve as both diagnostics and therapeutics; however, their diagnostic potential is often limited by tissue-associated light absorption and scattering. Herein, we develop CuInSe2@ZnS:Mn quantum dots (QDs) with intrinsic multifunctionality that both enable the accurate localization of small metastases and act as potent tumor ablation agents. By leveraging the growth kinetics of a ZnS shell on a biocompatible CuInSe2 core, Mn doping, and folic acid functionalization, we produce biocompatible QDs with high near-infrared (NIR)-II fluorescence efficiency up to 31.2%, high contrast on magnetic resonance imaging (MRI), and preferential distribution in 4T1 breast cancer tumors. MRI-enabled contrast of these nanoprobes is sufficient to timely identify small metastases in the lungs, which is critically important for preventing cancer spreading and recurrence. Further, exciting tumor-resident QDs with NIR light produces both fluorescence for tumor visualization through radiative recombination pathways as well as heat and radicals through nonradiative recombination pathways that kill cancer cells and initiate an anticancer immune response, which eliminates tumor and prevents tumor regrowth in 80% of mice.

• Klíčová slova
• NIR-II emission, cancer theranostics, exciton recombination pathways, intrinsic multifunctionality, semiconductor quantum dots,
• MeSH
• kvantové tečky * MeSH
• magnetická rezonanční tomografie metody   MeSH
• myši MeSH
• nádory * patologie   MeSH
• sloučeniny zinku MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• sloučeniny zinku MeSH
• zinc sulfide MeSH Prohlížeč

Background/Objectives: Dual-modality probes, combining positron emission tomography (PET) with fluorescence imaging (FI) capabilities in a single molecule, are of high relevance for the accurate staging and guided resection of tumours. We herein present a pair of candidates targeting the cholecystokinin-2 receptor (CCK2R), namely [68Ga]Ga-CyTMG and [68Ga]Ga-CyFMG. In these probes, the SulfoCy5.5 fluorophore and two units of a CCK2R-binding motif are coupled to the chelator acting as a core scaffold, triazacyclononane-phosphinic acid (TRAP), and Fusarinine C (FSC), respectively. Using this approach, we investigated the influence of these chelators on the final properties. Methods: The synthetic strategy to both precursors was based on the stoichiometric conjugation of the components via click chemistry. The characterization in vitro included the evaluation of the CCK2R affinity and internalization in A431-CCK2R cells. Ex vivo biodistribution as well as PET and FI studies were performed in xenografted mice. Results: 68Ga labelling was accomplished with high radiochemical yield and purity for both precursors. A CCK2R affinity in the subnanomolar range of the conjugates and a receptor-specific uptake of the radioligands in cells were observed. In A431-CCK2R/A431-mock xenografted mice, the investigated compounds showed specific accumulation in the tumours and reduced off-target uptake compared to a previously developed compound. Higher accumulation and prolonged retention in the kidneys were observed for [68Ga]Ga-CyTMG when compared to [68Ga]Ga-CyFMG. Conclusions: Despite the promising targeting properties observed, further probe optimization is required to achieve enhanced imaging contrast at early timepoints. Additionally, the results indicate a distinct influence of the chelators in terms of renal accumulation and retention.

• Klíčová slova
• FSC, PET, SulfoCy5.5, TRAP, cholecystokinin-2 receptor, dual-modality imaging agent, fluorescence guided surgery, gallium-68,
• Publikační typ
• časopisecké články MeSH

HYPOTHESIS: The development of bimodal imaging probes represents a hot topic of current research. Herein, we deal with developing an innovative bimodal contrast agent enabling fluorescence imaging (FI)/magnetic resonance imaging (MRI) and, simultaneously, consisting of biocompatible nanostructures. Optimized synthesis of advanced protein-embedded bimetallic (APEBM) nanocomposite containing luminescent gold nanoclusters (AuNC) and superparamagnetic iron oxide nanoparticles (SPION), suitable for in vivo dual-modal FI/MR imaging is reported. EXPERIMENTS: The APEBM nanocomposite was prepared by a specific sequential one-pot green synthetic approach that is optimized to increase metals (Au, Fe) content and, consequently, the imaging ability of the resulting nanostructures. The protein matrix, represented by serum albumin, was intentionally chosen, and used since it creates an efficient protein corona for both types of optically/magnetically-susceptible nanostructures (AuNC, SPION) and ensures biocompatibility of the resulting APEBM nanocomposite although it contains elevated metal concentrations (approx. 1 mg·mL-1 of Au, around 0.3 mg·mL-1 of Fe). In vitro and in vivo imaging was performed. FINDINGS: Successful in vivo FI and MRI recorded in healthy mice corroborated the applicability of the APEBM nanocomposite and, simultaneously, served as a proof of concept concerning the potential future exploitation of this new FI/MRI bimodal contrast agent in preclinical and clinical practice.

• Klíčová slova
• Bioimaging, Contrast agent, Fluorescent imaging, Inorganic-organic nanocomposite, Magnetic resonance imaging, Magneto-luminescent nanocomposite,
• MeSH
• kontrastní látky * chemie   MeSH
• magnetická rezonanční spektroskopie MeSH
• magnetická rezonanční tomografie metody   MeSH
• myši MeSH
• nanokompozity * chemie   MeSH
• optické zobrazování MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kontrastní látky * MeSH

Despite several attempts, in vivo bimodal imaging still represents a challenge. Generally, it is accepted that dual-modality in imaging can improve sensitivity and spatial resolution, namely, when exploiting fluorescence (FI) and magnetic resonance imaging (MRI), respectively. Here, a newly developed combination of (i) protein-protected luminescent Au-Ag nanoclusters (LGSN) manifesting themselves by fluorescent emission at 705 nm and (ii) superparamagnetic iron oxide nanoparticles (SPION) embedded within the same protein and creating contrast in MR images, has been investigated in phantoms and applied for in vivo bimodal imaging of a mouse as a proof of principle. Unique LGSN-SPION nanocomposites were synthesized in a specific sequential one-pot green preparation procedure and characterized thoroughly using many physicochemical experimental techniques. The influence of LGSN-SPION samples on the viability of healthy cells (RPE-1) was tested using a calcein assay. Despite the presence of Ag (0.12 mg mL-1), high content of Au (above 0.75 mg mL-1), and moderate concentrations of Fe (0.24 mg mL-1), LGSN-SPION samples (containing approx. 15 mg mL-1 of albumin) were revealed as biocompatible (cell viability above 80%). Simultaneously, these concentration values of all components in the LGSN-SPION nanocomposite were used for achieving both MRI and fluorescence signals in phantoms as well as in a living mouse with sufficiently high resolution. Thus, the LGSN-SPION samples can serve as new efficient bimodal FI and MRI probes for in vivo imaging.

• MeSH
• buněčné linie MeSH
• kontrastní látky chemie   MeSH
• lidé MeSH
• magnetická rezonanční tomografie * metody   MeSH
• myši MeSH
• nanokompozity * chemie   MeSH
• optické zobrazování MeSH
• stříbro * chemie   MeSH
• velikost částic MeSH
• viabilita buněk účinky léků   MeSH
• zlato * chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kontrastní látky MeSH
• stříbro * MeSH
• zlato * MeSH

Positron emission tomography (PET) as well as optical imaging (OI) with peptide receptor targeting probes have proven their value for oncological applications but also show restrictions depending on the clinical field of interest. Therefore, the combination of both methods, particularly in a single molecule, could improve versatility in clinical routine. This proof of principle study aims to show that a chelator, Fusarinine C (FSC), can be utilized as scaffold for novel dimeric dual-modality imaging agents. Two targeting vectors (a minigastrin analogue (MG11) targeting cholecystokinin-2 receptor overexpression (CCK2R) or integrin αVβ3 targeting cyclic pentapeptides (RGD)) and a near-infrared fluorophore (Sulfo-Cyanine7) were conjugated to FSC. The probes were efficiently labeled with gallium-68 and in vitro experiments including determination of logD, stability, protein binding, cell binding, internalization, and biodistribution studies as well as in vivo micro-PET/CT and optical imaging in U-87MG αVβ3- and A431-CCK2R expressing tumor xenografted mice were carried out. Novel bioconjugates showed high receptor affinity and highly specific targeting properties at both receptors. Ex vivo biodistribution and micro-PET/CT imaging studies revealed specific tumor uptake accompanied by slow blood clearance and retention in nontargeted tissues (spleen, liver, and kidneys) leading to visualization of tumors at early (30 to 120 min p.i.). Excellent contrast in corresponding optical imaging studies was achieved especially at delayed time points (24 to 72 h p.i.). Our findings show the proof of principle of chelator scaffolding for hybrid imaging agents and demonstrate FSC being a suitable bifunctional chelator for this approach. Improvements to fine-tune pharmacokinetics are needed to translate this into a clinical setting.

• MeSH
• chelátory chemie   farmakokinetika   MeSH
• heterografty MeSH
• integrin alfaVbeta3 metabolismus   MeSH
• kyseliny hydroxamové farmakokinetika   MeSH
• lidé MeSH
• molekulární sondy chemie   farmakokinetika   MeSH
• multimodální zobrazování metody   MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• nádory diagnostické zobrazování   metabolismus   MeSH
• PET/CT MeSH
• radioizotopy galia farmakokinetika   MeSH
• receptor cholecystokininu B metabolismus   MeSH
• železité sloučeniny farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chelátory MeSH
• fusigen MeSH Prohlížeč
• integrin alfaVbeta3 MeSH
• kyseliny hydroxamové MeSH
• molekulární sondy MeSH
• radioizotopy galia MeSH
• receptor cholecystokininu B MeSH
• železité sloučeniny MeSH

Tumor oxygenation and vascularization are important parameters that determine the aggressiveness of the tumor and its resistance to cancer therapies. We introduce dual-modality ultrasound and photoacoustic imaging (US-PAI) for the direct, non-invasive real-time in vivo evaluation of oxygenation and vascularization of patient-derived xenografts (PDXs) of B-cell mantle cell lymphomas. The different optical properties of oxyhemoglobin and deoxyhemoglobin make it possible to determine oxygen saturation (sO2) in tissues using PAI. High-frequency color Doppler imaging enables the visualization of blood flow with high resolution. Tumor oxygenation and vascularization were studied in vivo during the growth of three different subcutaneously implanted patient-derived xenograft (PDX) lymphomas (VFN-M1, VFN-M2 and VFN-M5 R1). Similar values of sO2 (sO2 Vital), determined from US-PAI volumetric analysis, were obtained in small and large VFN-M1 tumors ranging from 37.9 ± 2.2 to 40.5 ± 6.0 sO2 Vital (%) and 37.5 ± 4.0 to 35.7 ± 4.6 sO2 Vital (%) for small and large VFN-M2 PDXs. In contrast, the higher sO2 Vital values ranging from 57.1 ± 4.8 to 40.8 ± 5.7 sO2 Vital (%) (small to large) of VFN-M5 R1 tumors corresponds with the higher aggressiveness of that PDX model. The different tumor percentage vascularization (assessed as micro-vessel areas) of VFN-M1, VFN-M2 and VFN-M5 R1 obtained by color Doppler (2.8 ± 0.1%, 3.8 ± 0.8% and 10.3 ± 2.7%) in large-stage tumors clearly corresponds with their diverse growth and aggressiveness. The data obtained by color Doppler were validated by histology. In conclusion, US-PAI rapidly and accurately provided relevant and reproducible information on tissue oxygenation in PDX tumors in real time without the need for a contrast agent.

• Klíčová slova
• Mantle cell lymphoma, Patient-derived xenograft, Photoacoustic imaging, Tumor hypoxia, Tumor vascularization,
• MeSH
• hemoglobiny metabolismus   MeSH
• hypoxie buňky MeSH
• kyslík metabolismus   MeSH
• lidé MeSH
• lymfom z plášťových buněk diagnostické zobrazování   patologie   patofyziologie   MeSH
• mikrocévy diagnostické zobrazování   MeSH
• mikrovaskulární denzita MeSH
• multimodální zobrazování MeSH
• myši MeSH
• optoakustické techniky * MeSH
• oxyhemoglobiny metabolismus   MeSH
• patologická angiogeneze diagnostické zobrazování   MeSH
• transplantace nádorů MeSH
• tumor burden MeSH
• ultrasonografie dopplerovská barevná * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• deoxyhemoglobin MeSH Prohlížeč
• hemoglobiny MeSH
• kyslík MeSH
• oxyhemoglobiny MeSH