scholarly journals Multimerization Increases Tumor Enrichment of Peptide–Photosensitizer Conjugates

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 817 ◽  
Author(s):  
Jisi Zhao ◽  
Shuang Li ◽  
Yingying Jin ◽  
Jessica Wang ◽  
Wenjing Li ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Small Molecule ◽  
Tumor Targeting ◽  
Integrin Αvβ3 ◽  
Rgd Peptide ◽  
Therapeutic Modality ◽  
In Vivo Experiments ◽  
Small Molecule Ligands ◽  
Pyropheophorbide A

Photodynamic therapy (PDT) is an established therapeutic modality for the management of cancers. Conjugation with tumor-specific small molecule ligands (e.g., short peptides or peptidomimetics) could increase the tumor targeting of PDT agents, which is very important for improving the outcome of PDT. However, compared with antibody molecules, small molecule ligands have a much weaker affinity to their receptors, which means that their tumor enrichment is not always ideal. In this work, we synthesized multimeric RGD ligand-coupled conjugates of pyropheophorbide-a (Pyro) to increase the affinity through multivalent and cluster effects to improve the tumor enrichment of the conjugates. Thus, the dimeric and trimeric RGD peptide-coupled Pyro conjugates and the monomeric one for comparison were efficiently synthesized via a convergent strategy. A short polyethylene glycol spacer was introduced between two RGD motifs to increase the distance required for multivalence. A subsequent binding affinity assay verified the improvement of the binding towards integrin αvβ3 receptors after the increase in the valence, with an approximately 20-fold improvement in the binding affinity of the trimeric conjugate compared with that of the monomeric conjugate. In vivo experiments performed in tumor-bearing mice also confirmed a significant increase in the distribution of the conjugates in the tumor site via multimerization, in which the trimeric conjugate had the best tumor enrichment compared with the other two conjugates. These results indicated that the multivalence interaction can obviously increase the tumor enrichment of RGD peptide-conjugated Pyro photosensitizers, and the prepared trimeric conjugate can be used as a novel antitumor photodynamic agent with high tumor enrichment.

scholarly journals Integrin αvβ3-targeted polydopamine-coated gold nanostars for photothermal ablation therapy of hepatocellular carcinoma

2021 ◽  
Author(s):  
Yang Li ◽  
Ping Hu ◽  
Xiali Wang ◽  
Xu Hou ◽  
Fengzhen Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Integrin Αvβ3 ◽  
Rgd Peptide ◽  
Αvβ3 Integrin ◽  
Ablation Therapy ◽  
Gold Nanostars ◽  
In Vivo Experiments ◽  
Human Liver Cancer Cells

Abstract Photothermal therapy (PTT) has emerged as a promising cancer therapeutic method. In this study, Arg-Gly-Asp (RGD) peptide-conjugated polydopamine-coated gold nanostars (Au@PDA-RGD NPs) were prepared for targeting PTT of hepatocellular carcinoma (HCC). A polydopamine (PDA) shell was coated on the surface of gold nanostars by the oxidative self-polymerization of dopamine (termed as Au@PDA NPs). Au@PDA NPs were further functionalized with polyethylene glycol (PEG) and RGD peptide to improve biocompatibility as well as selectivity toward the HCC cells. Au@PDA-RGD NPs showed an intense absorption at 822 nm, which makes them suitable for NIR-excited PTT. Our results indicated that the Au@PDA-RGD NPs were effective for the PTT therapy of the αVβ3 integrin receptor-overexpressed HepG2 cells in vitro. Further antitumor mechanism studies showed that the Au@PDA-RGD NPs-based PTT induced human liver cancer cells death via the mitochondrial-lysosomal and autophagy pathways. In vivo experiments showed that Au@PDA-RGD NPs had excellent tumor treatment efficiency and negligible side effects. Thus, our study showed that Au@PDA-RGD NPs could offer an excellent nanoplatform for PTT of HCC.

scholarly journals Effect of Small-Molecule–Binding Affinity on Tumor Uptake In Vivo: A Systematic Study Using a Pretargeted Bispecific Antibody

2012 ◽  
Vol 11 (6) ◽  
pp. 1365-1372 ◽  
Author(s):  
Kelly Davis Orcutt ◽  
John J. Rhoden ◽  
Benjamin Ruiz-Yi ◽  
John V. Frangioni ◽  
K. Dane Wittrup
Keyword(s):  
Binding Affinity ◽  
Small Molecule ◽  
Systematic Study ◽  
Bispecific Antibody ◽  
Tumor Uptake

scholarly journals Investigation of Transcription Repression and Small-Molecule Responsiveness by TetR-Like Transcription Factors Using a Heterologous Escherichia coli-Based Assay

2007 ◽  
Vol 189 (18) ◽  
pp. 6655-6664 ◽  
Author(s):  
Sang Kyun Ahn ◽  
Kapil Tahlan ◽  
Zhou Yu ◽  
Justin Nodwell
Keyword(s):  
Escherichia Coli ◽  
Transcription Factors ◽  
Small Molecule ◽  
Target Genes ◽  
Streptomyces Coelicolor ◽  
Targeted Mutagenesis ◽  
E Coli ◽  
Small Molecule Ligands

ABSTRACT The SCO7222 protein and ActR are two of ∼150 TetR-like transcription factors encoded in the Streptomyces coelicolor genome. Using bioluminescence as a readout, we have developed Escherichia coli-based biosensors that accurately report the regulatory activity of these proteins and used it to investigate their interactions with DNA and small-molecule ligands. We found that the SCO7222 protein and ActR repress the expression of their putative target genes, SCO7223 and actII-ORF2 (actA), respectively, by interacting with operator sequence in the promoters. The operators recognized by the two proteins are related such that O 7223 (an operator for SCO7223) could be bound by both the SCO7222 protein and ActR with similar affinities. In contrast, Oact (an operator for actII-ORF2) was bound tightly by ActR and more weakly by the SCO7222 protein. We demonstrated ligand specificity of these proteins by showing that while TetR (but not ActR or the SCO7222 protein) interacts with tetracyclines, ActR (but not TetR or the SCO7222 protein) interacts with actinorhodin and related molecules. Through operator-targeted mutagenesis, we found that at least two nucleotide changes in O 7223 were required to disrupt its interaction with SCO7222 protein, while ActR was more sensitive to changes on Oact . Most importantly, we found that the interaction of each protein with wild-type and mutant operator sequences in vivo and in vitro correlated perfectly. Our data suggest that E. coli-based biosensors of this type should be broadly applicable to TetR-like transcription factors.

scholarly journals Alendronate/cRGD-Decorated Ultrafine Hyaluronate Dot Targeting Bone Metastasis

Biomedicines ◽  
2020 ◽  
Vol 8 (11) ◽  
pp. 492
Author(s):  
Eunsol Lee ◽  
Jaeduk Park ◽  
Yu Seok Youn ◽  
Kyung Taek Oh ◽  
Dongin Kim ◽  
...  
Keyword(s):  
Tumor Targeting ◽  
Bone Tumors ◽  
Tumor Therapy ◽  
Integrin Αvβ3 ◽  
Tumor Ablation ◽  
Cell Permeability ◽  
Cellular Interactions ◽  
Targeting Efficiency ◽  
Specific Ligand

In this study, we report the hyaluronate dot (dHA) with multiligand targeting ability and a photosensitizing antitumor model drug for treating metastatic bone tumors. Here, the dHA was chemically conjugated with alendronate (ALN, as a specific ligand to bone), cyclic arginine-glycine-aspartic acid (cRGD, as a specific ligand to tumor integrin αvβ3), and photosensitizing chlorin e6 (Ce6, for photodynamic tumor therapy), denoted as (ALN/cRGD)@dHA-Ce6. These dots thus prepared (≈10 nm in diameter) enabled extensive cellular interactions such as hyaluronate (HA)-mediated CD44 receptor binding, ALN-mediated bone targeting, and cRGD-mediated tumor integrin αvβ3 binding, thus improving their tumor targeting efficiency, especially for metastasized MDA-MB-231 tumors. As a result, these dots improved the tumor targeting efficiency and tumor cell permeability in a metastatic in vivo tumor model. Indeed, we demonstrated that (ALN/cRGD)@dHA-Ce6 considerably increased photodynamic tumor ablation, the extent of which is superior to that of the tumor ablation of dot systems with single or double ligands. These results indicate that dHA with multiligand can provide an effective treatment strategy for metastatic bone tumors.

Identification and in vivo efficacy of small-molecule antagonists of integrin αvβ3 (the vitronectin receptor)

2000 ◽  
Vol 5 (9) ◽  
pp. 397-408 ◽  
Author(s):  
William H Miller ◽  
Richard M Keenan ◽  
Robert N Willette ◽  
Michael W Lark
Keyword(s):  
Small Molecule ◽  
Integrin Αvβ3 ◽  
Vitronectin Receptor ◽  
In Vivo Efficacy

scholarly journals IR783 Encapsulated in TR-conjugated Liposomes for Enhancing NIR Imaging-guided Photothermal and Photodynamic Therapy

2021 ◽  
Author(s):  
Jiajia Lv ◽  
Tianjiao Luan ◽  
Mingyan Yang ◽  
Mengmeng Wang ◽  
Jie Gao ◽  
...  
Keyword(s):  
Tumor Therapy ◽  
Integrin Αvβ3 ◽  
Reticuloendothelial System ◽  
In Vivo Experiments ◽  
Nir Imaging ◽  
Diagnostic Agents ◽  
Tumor Selectivity ◽  
Physical And Chemical

Abstract We developed an integrin αvβ3-specific liposomes, TR-conjugated liposomes (TR-LPs), loading IR783 for NIR imaging-guided both PTT and PDT. The TR-LPs was composed of soyabeanphosphatidylcholine, cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine- N- [methoxy(polyethylene glycol)-2000] (DSPE-PEG) and TR-functionalized DSPE-PEG. IR783, NIR PTT/PDT diagnostic agents, were encapsulated in the hydrophilic core of the TR-LPs. DSPE-PEG had ability of reducing the absorption of TR-LPs by the reticuloendothelial system and increase the cycle time in body. RGD fragment on the TR peptide (TR = c(RGD)-AGYLLGHINLHHLAHL(Aib)HHIL-cys) enhanced the tumor selectivity of liposomes by specifically targeting integrin αvβ3-overexpressing cancer cells. Simultaneously, the rest of fragment on the TR peptide can be changed to the positive charge in the tumor microenvironment (pH 6.5), improving cellular uptake of photoagents at tumor site. We executed a set of in vitro and in vivo experiments to verify if, by functionalizing liposomes with an integrin αvβ3-specific and pH responding peptide, it is possible to achieve NIR imaging guided PTT/PDT for tumor treatment. TR-conjugated liposomes exhibited favorable physical and chemical stability, loading capacity, biocompatibility and tumor targeting. TR-LPs can safely and efficiently delivery IR783 to tumor sites to achieve their therapeutic function. IR783-TR-LPs is promising as a potentially safe and effective phototherapeutic agents for NIR fluorescence-guided tumor therapy applications.

scholarly journals Anti-Cancer Activities of Thyrointegrin αvβ3 Antagonist Mono- and Bis-Triazole Tetraiodothyroacetic Acid Conjugated via Polyethylene Glycols in Glioblastoma

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2780
Author(s):  
Kavitha Godugu ◽  
Mehdi Rajabi ◽  
Shaker A. Mousa
Keyword(s):  
Tumor Cells ◽  
Binding Affinity ◽  
Integrin Αvβ3 ◽  
Polyethylene Glycols ◽  
Primary Glioblastoma ◽  
Anticancer Properties ◽  
Biological Studies ◽  
Anti Cancer ◽  
Potential Cancer

Integrin αvβ3 receptors are overexpressed in different tumors and their associated neovascularization and hence, represent a potential cancer target. We previously synthesized a high affinity thyrointegrin αvβ3, P4000-bi-TAT (tetrac derivative), with potent anticancer properties. However, the long polydisperse PEG conjugate showed large scaleup and analytical/bioanalytical issues. Hence, in the present study, we synthesized a mono versus bi-triazole tetrac with discrete monodisperse PEG, which provided improvement in scaleup and bioanalysis. In the present study, we compared binding affinity and anticancer activates with a smaller PEG size (P1600-bi-TAT, Compound 2) and the removal of one TAT molecule (P1600-m-TAT, Compound 3) versus P4000-bi-TAT, Compound 1. The results of the selectivity and affinity of TATs showed greater affinity to integrin αvβ3. The xenograft weights and tumor cell viabilities were decreased by >90% at all doses compared to the control (ON Treatment, *** p < 0.001) in cells treated with Compounds 1, 2, and 3 in U87-Luc-treated mice. The in vivo luminescent signals of U87-luc cells reflect the proliferation and distribution of tumor cells in the animals and the maximum intensity corresponding to the maximum tumor cells that the animals could tolerate. We found that the three thyrointegrin αvβ3 antagonists exhibited optimal therapeutic efficacy against U87 or primary glioblastoma cells. Biological studies showed that decreasing the PEG linker size (1600 vs. 4000) or having mono-TAT or bi-TAT had no significant impact on their αvβ3 binding affinity, anti-angiogenesis, or overall anti-cancer efficacy.

scholarly journals Small Molecule Fluorescent Probes for G- Quadruplex Visualization as Potential Cancer Theranostic Agents

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 752 ◽  
Author(s):  
Pallavi Chilka ◽  
Nakshi Desai ◽  
Bhaskar Datta
Keyword(s):  
Small Molecule ◽  
Fluorescent Probes ◽  
Cancer Prognosis ◽  
Fluorescence Signal ◽  
Physiological Relevance ◽  
G Quadruplex ◽  
Small Molecule Ligands ◽  
Recent Developments ◽  
Theranostic Agents

G-quadruplexes have gained prominence over the past two decades for their role in gene regulation, control of anti-tumour activity and ageing. The physiological relevance and significance of these non-canonical structures in the context of cancer has been reviewed several times. Putative roles of G-quadruplexes in cancer prognosis and pathogenesis have spurred the search for small molecule ligands that are capable of binding and modulating the effect of such structures. On a related theme, small molecule fluorescent probes have emerged that are capable of selective recognition of G-quadruplex structures. These have opened up the possibility of direct visualization and tracking of such structures. In this review we outline recent developments on G-quadruplex specific small molecule fluorescent probes for visualizing G-quadruplexes. The molecules represent a variety of structural scaffolds, mechanism of quadruplex-recognition and fluorescence signal transduction. Quadruplex selectivity and in vivo imaging potential of these molecules places them uniquely as quadruplex-theranostic agents in the predominantly cancer therapeutic context of quadruplex-selective ligands.

scholarly journals Targeting dysregulation signatures of p53-MDM2 interactions to identify newer small molecule inhibitors for cancer therapy: Insight from computational direction

2021 ◽  
Author(s):  
Prosper Obed Chukwuemeka ◽  
Haruna Isiyaku Umar ◽  
Opeyemi Iwaloye ◽  
Oluwaseyi Matthew Oretade ◽  
Christopher Busayo Olowosoke ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Therapeutic Option ◽  
Pharmacophore Model ◽  
In Vivo Studies ◽  
Hydrogen Bond Acceptor ◽  
Potential Inhibitors

Abstract Dysregulation of the p53-MDM2 interactions has been implicated in majority of human tumors presenting a target for finding small molecule inhibitors. In this study, a training set of 17 experimentally tested inhibitors of MDM2 was used to develop series of pharmacophore models among which a four-featured (AHRR_1) model with one hydrogen bond acceptor, one hydrophobic group and two aromatic ring features and characterized by a survival score of 4.176 was considered significant among the top ranked generated hypothesis. Further, the model was validated by an external set of actives and decoy molecules and was found to exhibit encouraging statistical attributes (such as AUC > 0.7, BEDROC > 0.5 and EF > 1.0 etc). The model was used to screen the ZINC compound database, from the database, the top best 1375 hits satisfying the pharmacophore model was were docked to MDM2 protein to identify the likely interactions of the compounds as well as their binding affinity with MDM2. Further, druglikeness and pharmacokinetic properties screening on top-ranked compounds with higher binding affinity than reference inhibitors revealed four compounds (ZINC02639178, ZINC38933175, ZINC77969611, and ZINC06752762) with suitable pharmacological properties including low ligand toxicity. Investigation of the dynamic behaviour of each candidate inhibitors in complex with MDM2 via molecular dynamic simulation suggested ZINC02639178 and ZINC06752762 as the most potential inhibitors. Thus, these compounds may emerged as therapeutic option for cancer treatment after extensive in vitro and in vivo studies.

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