Zinc oxide nanoparticles functionalized with cinnamic acid for targeting dental pathogens receptor and modulating apoptotic genes in human oral epidermal carcinoma KB cells.

BACKGROUND: Oral diseases are often attributed to dental pathogens such as S. aureus, S. mutans, E. faecalis, and C. albicans. In this research work, a novel approach was employed to combat these pathogens by preparing zinc oxide nanoparticles (ZnO NPs) capped with cinnamic acid (CA) plant compounds. METHODS: The synthesized ZnO-CA NPs were characterized using SEM, FTIR, and XRD to validate their composition and structural features. The antioxidant activity of ZnO-CA NPs was confirmed using DPPH and ABTS free radical scavenging assays. The antimicrobial effects of ZnO-CA NPs were validated using a zone of inhibition assay against dental pathogens. Autodock tool was used to identify the interaction of cinnamic acid with dental pathogen receptors. RESULTS: ZnO-CA NPs exhibited potent antioxidant activity in both DPPH and ABTS assays, suggesting their potential as powerful antioxidants. The minimal inhibitory concentration of ZnO-CA NPs against dental pathogens was found 25 µg/mL, indicating their effective antimicrobial properties. Further, ZnO-CA NPs showed better binding affinity and amino acid interaction with dental pathogen receptors. Also, the ZnO-CA NPs exhibited dose-dependent (5 µg/mL, 15 µg/mL, 25 µg/mL, and 50 µg/mL) anticancer activity against Human Oral Epidermal Carcinoma KB cells. The mechanism of action of apoptotic activity of ZnO-CA NPs on the KB cells was identified through the upregulation of BCL-2, BAX, and P53 genes. CONCLUSIONS: This research establishes the potential utility of ZnO-CA NPs as a promising candidate for dental applications. The potent antioxidant, anticancer, and effective antimicrobial properties of ZnO-CA NPs make them a valuable option for combating dental pathogens.

Investigating the Anticancer Potential of Biochanin A in KB Oral Cancer Cells Through the NFκB Pathway.

Squamous cell carcinoma (SCC) is a malignancy primarily affecting squamous cells. Its development is linked to multiple risk factors, such as alcohol and tobacco consumption, human papillomavirus (HPV) infection, and Epstein-Barr Virus (EBV) infection. Biochanin A (BCA), a phytoestrogen extracted from red clover, has been extensively researched for its therapeutic properties. It spans antioxidant activity, anti-inflammatory effects, neuroprotection, cardioprotection, and anticancer potential in different bodily systems. However, its impact on oral cancer remains unexplored. Therefore, this investigation aims to assess the potential anticancer effects of BCA, specifically on KB oral cancer cells. This study utilized KB cells to evaluate the impact of BCA on various cellular parameters, including cell viability, apoptosis, intracellular ROS production, mitochondrial membrane potential, and cell migration. BCA treatment induced several notable effects on KB cells, including reduced cell viability, altered morphology suggestive of apoptosis, heightened oxidative stress, and alterations in mitochondrial membrane potential. Moreover, BCA treatment demonstrated an inhibitory effect on cell migration. The study further investigated the impact of BCA on antioxidant enzyme activities and lipid peroxidation, revealing decreased antioxidant enzyme activities and increased lipid peroxidation across different BCA concentrations (IC50 and IC90). Immunocytochemistry and qRT-PCR analyses unveiled that BCA treatment at varying doses (IC50 and IC90) downregulated the expression of nuclear factor-κB (NF-κB) subunits p50 and p65, pivotal players in cancer progression. In summary, this study sheds light on the promising potential of BCA as an anticancer therapeutic agent for treating oral cancer. Its demonstrated ability to induce apoptosis, perturb cellular functions, and modulate gene expression within cancer cells underscores its significance. Nonetheless, further research, particularly following animal studies, is imperative to comprehensively grasp the breadth of BCA's effects and its viability for clinical applications.

Synthesis and Preclinical Evaluation of [18F]AlF-NOTA-Asp2-PEG2-Folate as a Novel Folate-Receptor-Targeted Tracer for PET Imaging.

Recently, the folate receptor (FR) has become an exciting target for the diagnosis of FR-positive malignancies. Nevertheless, suboptimal in vivo pharmacokinetic properties, particularly high uptake in the renal and hepatobiliary systems, are important limiting factors for the clinical translation of most FR-based radiotracers. In this study, we developed a novel 18F-labeled FR-targeted positron emission tomography (PET) tracer [18F]AlF-NOTA-Asp2-PEG2-Folate modified with a hydrophilic linker (-Asp2-PEG2) to optimize its pharmacokinetic properties and conducted a comprehensive preclinical assessment. The [18F]AlF-NOTA-Asp2-PEG2-Folate was manually synthesized within 30 min with a non-decay-corrected radiochemical yield of 16.3 ± 2.0% (n = 5). Among KB cells, [18F]AlF-NOTA-Asp2-PEG2-Folate exhibited high specificity and affinity for FR. PET/CT imaging and biodistribution experiments in KB tumor-bearing mice showed decent tumor uptake (1.7 ± 0.3% ID/g) and significantly decreased uptake in kidneys and liver (22.2 ± 2.1 and 0.3 ± 0.1% ID/g at 60 min p.i., respectively) of [18F]AlF-NOTA-Asp2-PEG2-Folate, compared to the known tracer [18F]AlF-NOTA-Folate (78.6 ± 5.1 and 5.3 ± 0.5 % ID/g at 90 min p.i., respectively). The favorable properties of [18F]AlF-NOTA-Asp2-PEG2-Folate, including its efficient synthesis, decent tumor uptake, relatively low renal uptake, and rapid clearance from most normal organs, portray it as a promising PET tracer for FR-positive tumors.

Piperine-coated zinc oxide nanoparticles target biofilms and induce oral cancer apoptosis via BCl-2/BAX/P53 pathway.

BACKGROUND: Dental pathogens play a crucial role in oral health issues, including tooth decay, gum disease, and oral infections, and recent research suggests a link between these pathogens and oral cancer initiation and progression. Innovative therapeutic approaches are needed due to antibiotic resistance concerns and treatment limitations. METHODS: We synthesized and analyzed piperine-coated zinc oxide nanoparticles (ZnO-PIP NPs) using UV spectroscopy, SEM, XRD, FTIR, and EDAX. Antioxidant and antimicrobial effectiveness were evaluated through DPPH, ABTS, and MIC assays, while the anticancer properties were assessed on KB oral squamous carcinoma cells. RESULTS: ZnO-PIP NPs exhibited significant antioxidant activity and a MIC of 50 µg/mL against dental pathogens, indicating strong antimicrobial properties. Interaction analysis revealed high binding affinity with dental pathogens. ZnO-PIP NPs showed dose-dependent anticancer activity on KB cells, upregulating apoptotic genes BCL2, BAX, and P53. CONCLUSIONS: This approach offers a multifaceted solution to combatting both oral infections and cancer, showcasing their potential for significant advancement in oral healthcare. It is essential to acknowledge potential limitations and challenges associated with the use of ZnO NPs in clinical applications. These may include concerns regarding nanoparticle toxicity, biocompatibility, and long-term safety. Further research and rigorous testing are warranted to address these issues and ensure the safe and effective translation of ZnO-PIP NPs into clinical practice.

Synthesis, biological evaluation, and correlation of cytotoxicity versus redox potential of 1,4-naphthoquinone derivatives.

A series of 1,4-naphthoquinone derivatives of lawsone (1), 6-hydroxy-1,4-naphthoquinone (2), and juglone (3) were synthesized by alkylation, acylation, and sulfonylation reactions. The yields of lawsone derivatives 1a-1k (type A), 6-hydroxy-1,4-naphthoquinone derivatives 2a-2j (type B), and juglone derivatives 3a-3h (type C) were 52-99%, 53-96%, and 28-95%, respectively. All compounds were tested in vitro for the cytotoxicity against human oral epidermoid carcinoma (KB) and cervix epithelioid carcinoma (HeLa) cells and their structure-activity relationship was studied. Compound 3c was found to be most potent in KB cell line (IC50 = 1.39 µM). Some compounds were evaluated for DNA topoisomerase I inhibition. Compounds 2c, 3, 3a, and 3d showed topoisomerase inhibition activity with IC50 values of 8.3-91 µM. Standard redox potentials (E°) of all naphthoquinones in phosphate buffer at pH 7.2 were examined by means of cyclic voltammetry. A definite correlation has been found between the redox potentials and inhibitory effects of type A compounds.

Synthesis and biological evaluation of novel cabazitaxel analogues.

Cabazitaxel is one of the most recently FDA-approved taxane anticancer agent. In view of the advantages in preclinical and clinical data of cabazitaxel over former toxoids, the synthesis and biological evaluation of novel cabazitaxel analogues were conducted. First, a novel semi-synthesis of cabazitaxel was described. This strategy is concise and efficient, which needs five steps from the 10-deacetylbaccatin III (10-DAB) moiety and a commercially available C13 side chain precursor with a 32% overall yield. Besides, this strategy avoids using many hazardous reagents that involved in the previously reported processes. Then, a panel of cabazitaxel analogues were prepared basing on this strategy. The cytotoxicity evaluations showed that the majority of these cabazitaxel analogues are potent against both A549 and KB cells and their corresponding drug-resistant cell lines KB/VCR, and A549/T, respectively. Further in vivo antitumor efficacies assessment of 7,10-di-O-methylthiomethyl (MTM) modified cabazitaxel (compounds 16 and 19) on SCID mice A549 xenograft model showed they both had similar antitumor activity to the cabazitaxel. Since compound 19 was observed causing more body wight loss on the mice than 16, these preliminary studies suggest 16 might be a potent drug candidate for further preclinical evaluation.

Solid-phase synthesis and bioactivity evaluation of cherimolacyclopeptide E.

Cherimolacylopeptide E (1) is a cyclic hexapeptide isolated from the seeds of Annona cherimola. Peptide 1 reportedly exhibits potent cytotoxicity against KB cells (IC50 0.017 µM). To confirm the structure and bioactivity of 1, we conducted a total synthesis of its proposed structure. The synthesis was accomplished via solid-phase peptide elongation and macrocyclization by employing Fmoc/OAll-protected amino acids on 2-Cl-trityl resin. NMR analysis revealed that synthetic 1 exists in two conformations in pyridine-d5 . As the spectroscopic data of the major conformer of synthetic 1 were consistent with those of natural 1, the structure of cherimolacyclopeptide E was confirmed to be 1. However, our synthetic 1 exhibited low cytotoxicity against KB cells (IC50 > 100 µM). In contrast to previously-reported findings, our synthetic 1 exhibited little antibacterial activity against Escherichia coli.

Preparation and Evaluation of Novel Folate Isonitrile 99mTc Complexes as Potential Tumor Imaging Agents to Target Folate Receptors.

In order to seek novel technetium-99m folate receptor-targeting agents, two folate derivatives (CN5FA and CNPFA) were synthesized and radiolabeled to obtain [99mTc]Tc-CN5FA and [99mTc]Tc-CNPFA complexes, which exhibited high radiochemical purity (>95%) without purification, hydrophilicity, and good stability in vitro. The KB cell competitive binding experiments indicated that [99mTc]Tc-CN5FA and [99mTc]Tc-CNPFA had specificity to folate receptor. Biodistribution studies in KB tumor-bearing mice illustrated that [99mTc]Tc-CN5FA and [99mTc]Tc-CNPFA had specific tumor uptake. Compared with [99mTc]Tc-CN5FA, the tumor/muscle ratios of [99mTc]Tc-CNPFA were higher, resulting in a better SPECT/CT imaging background. According to the results, the two 99mTc complexes have potential as tumor imaging agents to target folate receptors.

In-Cell Generation of Anticancer Phenanthridine Through Bioorthogonal Cyclization in Antitumor Prodrug Development.

Pharmacological inactivation of antitumor drugs toward healthy cells is a critical factor in prodrug development. Typically, pharmaceutical chemists graft temporary moieties to existing antitumor drugs to reduce their pharmacological activity. Here, we report a platform able to generate the cytotoxic agent by intramolecular cyclization. Using phenanthridines as cytotoxic model compounds, we designed ring-opened biaryl precursors that generated the phenanthridines through bioorthogonal irreversible imination. This reaction was triggered by reactive oxygen species, commonly overproduced in cancer cells, able to convert a vinyl boronate ester function into a ketone that subsequently reacted with a pendant aniline. An inactive precursor was shown to engender a cytotoxic phenanthridine against KB cancer cells. Moreover, the kinetic of cyclization of this prodrug was extremely rapid inside living cells of KB cancer spheroids so as to circumvent drug action.

Pd-Catalyzed Decarboxylative Olefination: Stereoselective Synthesis of Polysubstituted Butadienes and Macrocyclic P-glycoprotein Inhibitors.

The efficient and stereoselective synthesis of polysubstituted butadienes, especially the multifunctional butadienes, represents a great challenge in organic synthesis. Herein, we wish to report a distinctive Pd(0) carbene-initiated decarboxylative olefination approach that enables the direct coupling of diazo esters with vinylethylene carbonates (VECs), vinyl oxazolidinones, or vinyl benzoxazinones to afford alcohol-, amine-, or aniline-containing 1,3-dienes in moderate to high yields and with excellent stereoselectivity. This protocol features operational simplicity, mild reaction conditions, a broad substrate scope, and gram-scalability. Notably, a structurally unique allylic Pd(II) intermediate was isolated and characterized. DFT calculation and control experiments demonstrated that a rare Pd(0) carbene intermediate could be involved in this reaction. Moreover, the polysubstituted butadienes as novel building blocks were unprecedentedly assembled into macrocycles, which efficiently inhibited the P-glycoprotein and dramatically reversed multidrug resistance in cancer cells by 190-fold.

Folate-conjugated herpes simplex virus for retargeting to tumor cells.

BACKGROUND: Herpes simplex virus type 1 (HSV-1)-mediated oncolytic therapy is a promising cancer treatment modality. However, viral tropism is considered to be one of the major stumbling blocks to the development of HSV-1 as an anticancer agent. METHODS: The surface of oncolytic HSV-1 G207 was covalently modified with folate-poly (ethylene glycol) conjugate (FA-PEG). The specificities and tumor targeting efficiencies of modified or unmodified G207 particles were analyzed by a real-time polymerase chain reaction at the level of cell attachment and entry. Immune responses were assessed by an interleukin-6 release assay from RAW264.7 macrophages. Biodistribution and in vivo antitumoral activity after intravenous delivery was evaluated in BALB/c nude mice bearing subcutaneous KB xenograft tumors. RESULTS: FA-PEG-HSV exhibited enhanced targeting specificity for folate receptor over-expressing tumor cells and had lower immunogenicity than the unmodified HSV. In vivo, the FA-PEG-HSV group revealed an increased anti-tumor efficiency and tumor targeting specificity compared to the naked HSV. CONCLUSIONS: These results indicate that folate-conjugated HSV G207 presents a folate receptor-targeted oncolytic virus with a potential therapeutic value via retargeting to tumor cells.

Raphanus sativus L. seed extracts induce apoptosis and reduce migration of oral squamous cell carcinoma KB and KBCD133+cells by downregulation of ß-catenin.

Although, oral cancer therapies have been developed for decades, patient survival rates have not changed. Side effects of chemotherapy and radiotherapy reduce quality of life of patients and it remains difficult to treat oral cancers due to the presence of cancer stem cells (CSCs) that cause recurrence and metastasis. Therefore, we search for natural products that affect oral cancer cells including oral cancer stem cells. In the present study, we investigated the anticancer effects of Raphanus sativus L. seed (RSLS) extracts on oral squamous cell carcinoma KB cells and CSC-like KBCD133+ cells. CD133 plays an important role in CSCs and physically binds to ß-catenin to activate the ß-catenin signaling targets. Therefore, a natural extract that can inhibit ß-catenin act in may be effective anticancer drug acquiring CSC. Of the natural product extract candidates, RSLS extracts induced apoptosis in KB and KBCD133+ cells and inhibited nuclear translocation of ß-catenin cell migration and invasion rates. Treatment of RSLS extracts resulted in increases of Axin and it leds to reductions of ß-catenin in KB and KBCD133+ cells. Hence, the result suggests that RSLS are potential candidate for anticancer drug against oral cancer cells and CSCs.AbbreviationsCSCcancer stem cellsOSCCsquamous cell carcinoma cellsRSLSRaphanus sativus L. seed.

Pharmacokinetic Properties of 68Ga-labelled Folic Acid Conjugates: Improvement Using HEHE Tag.

The folate receptor (FR) is a promising cell membrane-associated target for molecular imaging and radionuclide therapy of cancer (FR-α) and potentially also inflammatory diseases (FR-ß) through use of folic acid-based radioconjugate. FR is often overexpressed by cells of epithelial tumors, including tumors of ovary, cervix, endometrium, lungs, kidneys, etc. In healthy tissues, FR can be found in small numbers by the epithelial cells, mainly in the kidneys. Extremely high undesired accumulation of the folate radioconjugates in the renal tissue is a main drawback of FR-targeting concept. In the course of this work, we aimed to reduce the undesirable accumulation of folate radioconjugates in the kidneys by introducing a histidine/glutamic acid tag into their structure. Two folic acid based compounds were synthesized: NODAGA-1,4-butanediamine-folic acid (FA-I, as control) and NODAGA-[Lys-(HE)2]-folic acid (FA-II) which contains a (His-Glu)2 fragment. In vitro studies with FR (+) cells (KB and others) showed that both compounds have specificity for FR. Introduction of (HE)2-tag does not affect FR binding ability of the conjugates. In vivo biodistribution studies with normal laboratory animals, as well as with KB tumor bearing animals, were carried out. The results showed that introduction of the (HE)2 tag into the structure of folate radioconjugates can significantly reduce the accumulation of these compounds in non-target tissues and important organs (the accumulation in the kidneys is reduced 2-4 times), leaving the accumulation in tumor at least at the same level, and even increasing it.

Naringin-loaded polymeric micelles as buccal tablets: formulation, characterization, in vitro release, cytotoxicity and histopathology studies.

Naringin (NG) has been proved to have numerous notable biological effects, including anti-inflammatory effect, anti-cancer effect, and anti-ulcer effect, yet there are no clinical preparations of naringin due to its poor solubility and low dissolution rate after oral administration. In this study, in order to overcome these problems, NG was encapsulated into MPEG-PCL micelles (NGMs) by using a thin-film hydration method. NMGs were in a typical core-shell structure, with a mall particle size (23.95 ± 0.51 nm), high drug loading, and encapsulation efficiency. In vitro release of NGMs indicated that the dissolution of NG was increased after being encapsulated in the micelles. NGMs were nontoxic in the cytotoxicity and histopathology studies. Furthermore, when the freeze-dried NGMs were compressed into buccal tablets (NGBTs) by direct compression, the release speed of NG under simulated oral cavity condition from NGBTs was higher than the control tablets, with the accumulated dissolution at 93.13% in 8 hours. In conclusion, NGMs and NGBTs represent a promising drug delivery system for NG, which has the potential to improve the current treatment of oral diseases.

Probing Polarity and Heterogeneity of Lipid Droplets in Live Cells Using a Push-Pull Fluorophore.

Lipid droplets (LDs) are organelles composed of a lipid core surrounded by a phospholipid monolayer. Lately, LDs have attracted considerable attention due to recent studies demonstrating their role in a variety of physiological processes as well as diseases. Herein we synthesized a push-pull molecule named DAF (Dimethyl Aniline Furaldehyde) that possesses a strong positive solvatochromism in emission of 119 nm from toluene to methanol. Its impressive fluorogenic properties from water to oil (2000-fold) as well as its high quantum yields (up to 0.97) led us to investigate its ability to sense the distribution of polarity in live cells by fluorescence ratiometric imaging. When added to live cells and excited at 405 nm, DAF immediately and brightly stain lipid droplets using a blue channel (410-500 nm) and cytoplasm in a red channel (500-600 nm). DAF also proved to be compatible with fixation thus allowing 3D imaging of LDs in their cytoplasm environment. Taking advantage of DAF emission in two distinct channels, ratiometric imaging was successfully performed and led to the polarity mapping of the cell unraveling some heterogeneity in polarity within LDs of the same cell.

Viruslike Element-Tagged Nanoparticle Inductively Coupled Plasma Mass Spectrometry Signal Multiplier: Membrane Biomarker Mediated Cell Counting.

Although rare cancerous cells are considered as more objective indications for a precise early diagnosis of cancers, accurate counting of them still is a spirited challenge. We reported a signal multiplication strategy by constructing element-tagged viruslike nanoparticles (VLNPs) with a precise number of atoms for a membrane biomarker mediated higher sensitive cell counting using inductively coupled plasma mass spectrometry (ICPMS). Typical bacteriophage MS2 was exemplified to demonstrate the effectiveness of the element-tagged VLNPs as signal multipliers. Dibenzylcyclooctyne-poly(ethylene glycol)-folate (DBCO-PEG-FA) and DOTA-Eu complex tag modified (FA-PEG)69-MS2-(DOTA-Eu)965 targeted the folate receptor (FR) on KB cells as low as subzeptomole FRs could be quantified by 153Eu-species unspecific isotope dilution ICPMS, allowing us to be able to count at least 5 KB cells. While more than 2197 KB cells were needed to give a significant ICPMS signal using FA-PEG-DOTA-Eu, demonstrating more than 2 orders of magnitude signal multiplication and resulting in total 4.0 × 108 times signal amplification relative to one KB cell. We believe that such a signal multiplication strategy can be expanded to quantify and count other membrane biomarkers and their host cells using various VLNPs modified with different kinds and precise numbers of elements and guiding groups. In this way, prescribed multiples of signal amplification can be realized for a more accurate ICPMS-based quantitative bioanalysis because targeted molecules/cells in a complicated biological system might exist in orders of magnitude wide concentration range.

Reversal effect of FW-04-806, a macrolide dilactone compound, on multidrug resistance mediated by ABCB1 and ABCG2 in vitro and in vivo.

BACKGROUND: Overexpression of ATP-binding cassette (ABC) transporters, such as ABCB1 and ABCG2, has been proved to be a major trigger for multidrug resistance (MDR) in certain types of cancer. A promising approach to reverse MDR is the combined use of nontoxic and potent ABC transporters inhibitor with conventional anticancer drugs. We previously reported that FW-04-806 (conglobatin) as a novel Hsp90 inhibitor with low toxicity, capable of attenuating Hsp90/Cdc37 /clients interactions and producing antitumor action in vitro and in vivo. Our early activity screening found that FW-04-806 at non-cytotoxic concentration was able to enhance the cytotoxicity of chemotherapeutic agents on the ABCB1 overexpressing cells. Therefore, we speculated that FW-04-806 might be a promising MDR reversal agent. In the present study we further investigated its reversal effect of MDR induced by ABC transporters in vitro and in vivo. METHODS: MTT assay in vitro and xenograftes in vivo were used to investigate reversal effect of FW-04-806 on MDR in ABCB1 or ABCG2 overexpressing cancer cells. To understand the mechanisms for the MDR reversal, we examined the effects of FW-04-806 on intracellular accumulation of doxorubicin (DOX, adriamycin, adr)/Rhodamine 123 (Rho 123), efflux of doxorubicin, expression levels of gene and protein of ABCB1 or ABCG2 and ATPase activity of ABCB1, and carried out molecular docking between FW-04-806 and human ABCB1. RESULTS: The results indicated that FW-04-806 significantly enhanced the cytotoxicity of substrate chemotherapeutic agents on the ABCB1 or ABCG2 overexpressing cells in vitro and in vivo suggesting its reversal MDR effects. FW-04-806 increased the intracellular accumulation of DOX or Rho123 by inhibiting the efflux function of ABC transporters in MDR cells rather than in their parental sensitive cells. However, unlike other ABC transporter inhibitors, FW-04-806 had no effect on the ATPase activity nor on the expression of ABCB1 or ABCG2 on either mRNA or protein level. Molecular docking suggested that FW-04-806 may have lower affinity to the ATPase site, which was consistent with its no significant effect on the ATPase activity of ABCB1; However FW-04-806 may bind to substrate binding site in TMDs more stably than substrate anticancer drugs therefore obstruct the anticancer drugs pumped out of the cell. CONCLUSIONS: FW-04-806 is a compound that has both anti-tumor and reversal MDR effects, and its antitumor clinical application is worth further study.

Zwitterionic Polydopamine-Coated Manganese Oxide Nanoparticles with Ultrahigh Longitudinal Relaxivity for Tumor-Targeted MR Imaging.

We present the design of antifouling zwitterion-functionalized manganese oxide (Mn3O4) nanoparticles (NPs) modified with folic acid (FA) for targeted tumor magnetic resonance (MR) imaging. In the current work, diethylene glycol-stabilized Mn3O4 NPs were initially prepared via a solvothermal approach, coated with polydopamine (PDA), fluorescently labeled with rhodamine B, conjugated with FA via amide bond formation, and finally covered with zwitterions of l-lysine (Lys). The thus-generated multifunctional Mn3O4 NPs display excellent water dispersibility and colloidal stability, good protein resistance ability, and desirable cytocompatibility. With the PDA and Lys modifications, the multifunctional Mn3O4 NPs own an ultrahigh r1 relaxivity (89.30 mM-1 s-1) and enable targeted tumor MR imaging, owing to the linked FA ligands. The designed antifouling zwitterion-functionalized Mn3O4 NPs may be employed as an excellent MR contrast agent for targeted MR imaging of other biological systems.

Riboflavin-Terminated, Multivalent Quantum Dot as Fluorescent Cell Imaging Probe.

Bioconjugated nanoparticles are commonly used for targeting cellular/subcellular components, and labeling performance is known to depend on multivalency, i.e., the number of attached biomolecule per particle. However, these multivalency effects are largely unexplored. Here, we show that multivalency of nanoparticle-bound riboflavin controls the cellular interaction, cellular entry/exit mechanism, and subcellular trafficking property. We have synthesized riboflavin-functionalized quantum dot (QD) of 15-25 nm hydrodynamic size with average riboflavin multivalencies of 15, 30, and 70 [designated as QD(RF)15, QD(RF)30, and QD(RF)70, respectively] and investigated their uptake mechanism in riboflavin receptor overexpressed KB cells. We found that increased multivalency from 15 to 70 increases the cellular interaction with QD, shifts the cell uptake mechanism from caveolae-clathrin to exclusive clathrin-mediated endocytosis, and enhances lysosomal trafficking. This work demonstrates the importance of multivalency of bioconjugated molecule at the nanoparticle surface toward biolabeling performance and should be optimized for best performance of designed nanobioconjugate.

Development of 99mTc-labeled trivalent isonitrile radiotracer for folate receptor imaging.

Folate receptors (FR) are frequently overexpressed in a wide variety of human cancers. The aim of this study was to develop a trivalent 99mTc(CO)3-labeled folate radiotracer containing isonitrile (CN-R) as the coordinating ligand for FR target imaging. [99mTc]Tc-10 was HPLC purified (>98% chemical purity) and evaluated in vitro and in vivo as a potential agent for targeting FR-positive KB cells. [99mTc]Tc-10 is a hydrophilic compound with partition coefficient of -2.90 ±â€¯0.13 that showed high binding affinity (0.04 ±â€¯0.002 nM) in vitro. High accumulation and retention of [99mTc]Tc-10 (5.32 ±â€¯2.99% ID/g) was observed in mice with KB tumors at 4 h after injection through the tail vein, which was significantly inhibited by co-injection of free folic acid (FA). SPECT (single photon emission tomography)/CT results were in accordance with biodistribution data at all time points.