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1. Peptide-Mediated Targeting Mesoporous Silica Nanoparticles: A Novel Tool for Fighting Bladder Cancer

   Sweeney, Sean K ; Luo, Yi ; O'Donnell, Michael A ; Assouline, Jose G ( February 2017 , Journal of biomedical nanotechnology)

   Transitional cell carcinoma of the bladder is particularly devastating due to its high rate of recurrence and difficulty in retention of treatments within the bladder. Current cystoscopic approaches to detect and stage the tumor are limited by the penetrative depth of the cystoscope light source, and intravesical dyes that highlight tumors for surgical resection are non-specific. To address the needs for improved specificity in tumor detection and follow-up, we report on a novel technology relying on the engineered core of mesoporous silica (MSN) with surface modifications that generate contrast in fluorescence and magnetic resonance imaging (MRI). The particle surface was further functionalized to include a bladder cancer cell specific peptide, Cyc6, identified via phage display. This peptide possesses nanomolar specificity for bladder cancer cells and homology across multiple species including mouse, canine, and human. Our study takes advantage of its target expression in bladder tumor which is not expressed in normal bladder wall. When functionalized to MSN, the Cyc6 improved binding efficiency and specificity for bladder cancer cells in vitro. In an in vivo model, MSN instilled into bladders of tumor-bearing mice enhanced T 1- and T 2-weighted MRI signals, improving the detection of the tumor boundaries. These findings supportmore »the notion that our targeted nanomaterial presents new options for early detection and eventual therapeutic intervention. Ultimately, the combination of real-time and repeated MRI evaluation of the tumors enhanced by nanoparticle contrast have the potential for translation into human clinical studies for tumor staging, therapeutic monitoring, and drug delivery.« less
2. Click Conjugation of Boron Dipyrromethene (BODIPY) Fluorophores to EGFR-Targeting Linear and Cyclic Peptides

   https://doi.org/10.3390/molecules26030593  

   Williams, Tyrslai M. ; Kaufman, Nichole E. ; Zhou, Zehua ; Singh, Sitanshu S. ; Jois, Seetharama D. ; Vicente, Maria da ( February 2021 , Molecules)

   Through a simple 1,3-cycloaddition reaction, three BODIPY-peptide conjugates that target the extracellular domain of the epidermal growth factor receptor (EGFR) were prepared and their ability for binding to EGFR was investigated. The peptide ligands K(N3)LARLLT and its cyclic analog cyclo(K(N3)larllt, previously shown to have high affinity for binding to the extracellular domain of EGFR, were conjugated to alkynyl-functionalized BODIPY dyes 1 and 2 via a copper-catalyzed click reaction. This reaction produced conjugates 3, 4, and 5 in high yields (70–82%). In vitro studies using human carcinoma HEp2 cells that overexpress EGFR demonstrated high cellular uptake, particularly for the cyclic peptide conjugate 5, and low cytotoxicity in light (~1 J·cm−2) and darkness. Surface plasmon resonance (SPR) results show binding affinity of the three BODIPY-peptide conjugates for EGFR, particularly for 5 bearing the cyclic peptide. Competitive binding studies using three cell lines with different expressions of EGFR show that 5 binds specifically to EGFR-overexpressing colon cancer cells. Among the three conjugates, 5 bearing the cyclic peptide exhibited the highest affinity for binding to the EGFR protein.
3. Comparative Molecular Immunological Activity of Physiological Metal Oxide Nanoparticle and its Anticancer Peptide and RNA Complexes

   https://doi.org/10.3390/nano9121670  

   DeLong, Robert K. ; Comer, Jeffrey ; Mathew, Elza Neelima ; Jaberi-Douraki, Majid ( December 2019 , Nanomaterials)

   Currently, there is a great interest in nanoparticle-based vaccine delivery. Recent studies suggest that nanoparticles when introduced into the biological milieu are not simply passive carriers but may also contribute immunological activity themselves or of their own accord. For example there is considerable interest in the biomedical applications of one of the physiologically-based inorganic metal oxide nanoparticle, zinc oxide (ZnO). Indeed zinc oxide (ZnO) NP are now recognized as a nanoscale chemotherapeutic or anticancer nanoparticle (ANP) and several recent reports suggest ZnO NP and/or its complexes with drug and RNA induce a potent antitumor response in immuno-competent mouse models. A variety of cell culture studies have shown that ZnO NP can induce cytokines such as IFN-γ, TNF-α, IL-2, and IL-12 which are known to regulate the tumor microenvironment. Much less work has been done on magnesium oxide (MgO), cobalt oxide (Co3O4), or nickel oxide (NiO); however, despite the fact that these physiologically-based metal oxide NP are reported to functionally load and assemble RNA and protein onto their surface and may thus also be of potential interest as nanovaccine platform. Here we initially compared in vitro immunogenicity of ZnO and Co3O4 NP and their effects on cancer-associated or tolerogenic cytokines. Basedmore »on these data we moved ZnO NP forward to testing in the ex vivo splenocyte assay relative to MgO and NiO NP and these data showed significant difference for flow cytometry sorted population for ZnO-NP, relative to NiO and MgO. These data suggesting both molecular and cellular immunogenic activity, a double-stranded anticancer RNA (ACR), polyinosinic:poly cytidylic acid (poly I:C) known to bind ZnO NP; when ZnO-poly I:C was injected into B16F10-BALB/C tumor significantly induced, IL-2 and IL-12 as shown by Cohen’s d test. LL37 is an anticancer peptide (ACP) currently in clinical trials as an intratumoral immuno-therapeutic agent against metastatic melanoma. LL37 is known to bind poly I:C where it is thought to compete for receptor binding on the surface of some immune cells, metastatic melanoma and lung cells. Molecular dynamic simulations revealed association of LL37 onto ZnO NP confirmed by gel shift assay. Thus using the well-characterized model human lung cancer model cell line (BEAS-2B), poly I:C RNA, LL37 peptide, or LL37-poly I:C complexes were loaded onto ZnO NP and delivered to BEAS-2B lung cells, and the effect on the main cancer regulating cytokine, IL-6 determined by ELISA. Surprisingly ZnO-LL37, but not ZnO-poly I:C or the more novel tricomplex (ZnO-LL37-poly I:C) significantly suppressed IL-6 by >98–99%. These data support the further evaluation of physiological metal oxide compositions, so-called physiometacomposite (PMC) materials and their formulation with anticancer peptide (ACP) and/or anticancer RNA (ACR) as a potential new class of immuno-therapeutic against melanoma and potentially lung carcinoma or other cancers.« less
4. Mitochondrial Targeting Peptide-based Nanodelivery for Cancer Treatment

   https://doi.org/10.2174/1389203723666220520160435  

   Ehsan, Sumia ; Covarrubias-Zambrano, Obdulia ; Bossmann, Stefan H. ( October 2022 , Current Protein & Peptide Science)

   Abstract: Mitochondria are important intracellular organelles because of their key roles in cellular metabolism,proliferation, and programmed cell death. The differences in the structure and function of themitochondria of healthy and cancerous cells have made mitochondria an interesting target for drug delivery.Mitochondrial targeting is an emerging field as the targeted delivery of cytotoxic payloads andantioxidants to the mitochondrial DNA is capable of overcoming multidrug resistance. Mitochondrialtargeting is preferred over nuclear targeting because it can take advantage of the distorted metabolismin cancer. The negative membrane potential of the inner and outer mitochondrial membranes, as well astheir lipophilicity, are known to be the features that drive the entry of compatible targeting moiety,along with anticancer drug conjugates, towards mitochondria. The design of such drug nanocarrier conjugatesis challenging because they need not only to target the specific tumor/cancer site but have toovercome multiple barriers as well, such as the cell membrane and mitochondrial membrane. This reviewfocuses on the use of peptide-based nanocarriers (organic nanostructures such as liposomes, inorganic,carbon-based, and polymers) for mitochondrial targeting of the tumor/cancer. Both invitro and in vivo key results are reported.
5. Excitation ratiometric chloride sensing in a standalone yellow fluorescent protein is powered by the interplay between proton transfer and conformational reorganization

   https://doi.org/10.1039/D1SC00847A  

   Chen, Cheng ; Tutol, Jasmine N. ; Tang, Longteng ; Zhu, Liangdong ; Ong, Whitney S. ; Dodani, Sheel C. ; Fang, Chong ( January 2021 , Chemical Science)

   Natural and laboratory-guided evolution has created a rich diversity of fluorescent protein (FP)-based sensors for chloride (Cl − ). To date, such sensors have been limited to the Aequorea victoria green fluorescent protein (avGFP) family, and fusions with other FPs have unlocked ratiometric imaging applications. Recently, we identified the yellow fluorescent protein from jellyfish Phialidium sp. (phiYFP) as a fluorescent turn-on, self-ratiometric Cl − sensor. To elucidate its working mechanism as a rare example of a single FP with this capability, we tracked the excited-state dynamics of phiYFP using femtosecond transient absorption (fs-TA) spectroscopy and target analysis. The photoexcited neutral chromophore undergoes bifurcated pathways with the twisting-motion-induced nonradiative decay and barrierless excited-state proton transfer. The latter pathway yields a weakly fluorescent anionic intermediate , followed by the formation of a red-shifted fluorescent state that enables the ratiometric response on the tens of picoseconds timescale. The redshift results from the optimized π–π stacking between chromophore Y66 and nearby Y203, an ultrafast molecular event. The anion binding leads to an increase of the chromophore p K a and ESPT population, and the hindrance of conversion. The interplay between these two effects determines the turn-on fluorescence response to halides such as Cl −more »but turn-off response to other anions such as nitrate as governed by different binding affinities. These deep mechanistic insights lay the foundation for guiding the targeted engineering of phiYFP and its derivatives for ratiometric imaging of cellular chloride with high selectivity.« less