“Albumin Hitchhiking” with an Evans Blue Analog for Cancer Theranostics

Lan, Xiaoli; Cai, Weibo

doi:10.7150/thno.24183

Cited by 22 publications

(11 citation statements)

References 15 publications

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“…Here, we report a K D for human ACE2 that has an affinity that is 1,000-fold higher than for human albumin ( K D , 1.6 nM; see Table 1 ). A recent review has detailed the potential for Evans blue in biomedical applications ( 50 ), including imaging in cancer ( 51 , 52 ). Vero-E6 cell infection assays for SARS-CoV-2 show that Evans blue has an IC 50 value of 28.1 μM, with a CC 50 of greater than 1 mM.…”

Section: Discussionmentioning

confidence: 99%

Multidisciplinary Approaches Identify Compounds that Bind to Human ACE2 or SARS-CoV-2 Spike Protein as Candidates to Block SARS-CoV-2–ACE2 Receptor Interactions

Day

Bailly

Guillon

et al. 2021

mBio

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged virus that causes coronavirus infectious disease 2019 (COVID-19). SARS-CoV-2 spike protein, like SARS-CoV-1, uses the angiotensin converting enzyme 2 (ACE2) as a cellular receptor to initiate infection. Compounds that interfere with the SARS-CoV-2 spike protein receptor binding domain protein (RBD)-ACE2 receptor interaction may function as entry inhibitors. Here, we used a dual strategy of molecular docking and surface plasmon resonance (SPR) screening of compound libraries to identify those that bind to human ACE2 or the SARS-CoV-2 spike protein receptor binding domain (RBD). Molecular modeling screening interrogated 57,641 compounds and focused on the region of ACE2 that is engaged by RBD of the SARS-CoV-2 spike glycoprotein and vice versa. SPR screening used immobilized human ACE2 and SARS-CoV-2 Spike protein to evaluate the binding of these proteins to a library of 3,141 compounds. These combined screens identified compounds from these libraries that bind at KD (equilibrium dissociation constant) <3 μM affinity to their respective targets, 17 for ACE2 and 6 for SARS-CoV-2 RBD. Twelve ACE2 binders and six of the RBD binders compete with the RBD-ACE2 interaction in an SPR-based competition assay. These compounds included registered drugs and dyes used in biomedical applications. A Vero-E6 cell-based SARS-CoV-2 infection assay was used to evaluate infection blockade by candidate entry inhibitors. Three compounds demonstrated dose-dependent antiviral in vitro potency—Evans blue, sodium lifitegrast, and lumacaftor. This study has identified potential drugs for repurposing as SARS-CoV-2 entry inhibitors or as chemical scaffolds for drug development. IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, has caused more than 60 million cases worldwide with almost 1.5 million deaths as of November 2020. Repurposing existing drugs is the most rapid path to clinical intervention for emerging diseases. Using an in silico screen of 57,641 compounds and a biophysical screen of 3,141 compounds, we identified 22 compounds that bound to either the angiotensin converting enzyme 2 (ACE2) and/or the SARS-CoV-2 spike protein receptor binding domain (SARS-CoV-2 spike protein RBD). Nine of these drugs were identified by both screening methods. Three of the identified compounds, Evans blue, sodium lifitegrast, and lumacaftor, were found to inhibit viral replication in a Vero-E6 cell-based SARS-CoV-2 infection assay and may have utility as repurposed therapeutics. All 22 identified compounds provide scaffolds for the development of new chemical entities for the treatment of COVID-19.

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Section: Discussionmentioning

confidence: 99%

Multidisciplinary Approaches Identify Compounds that Bind to Human ACE2 or SARS-CoV-2 Spike Protein as Candidates to Block SARS-CoV-2–ACE2 Receptor Interactions

Day

Bailly

Guillon

et al. 2021

mBio

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“…Most PRRT studies have focused on G1 and G2 NENs (6)(7)(8)(24)(25)(26)(27). The NETTER-1 study, a prospective randomized controlled phase 3 clinical trial using tandem treatment with 177 Lu-DOTA-TATE and octreotide (long-acting release) (30 mg) in patients with advanced midgut neuroendocrine tumors, also focused on well-differentiated NENs; in that study, a markedly improved PFS and a significantly higher response rate were reported with the tandem treatment than with high-dose octreotide (long-acting release) (6).…”

Section: Discussionmentioning

confidence: 99%

Peptide Receptor Radionuclide Therapy in Grade 3 Neuroendocrine Neoplasms: Safety and Survival Analysis in 69 Patients

et al. 2018

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To date, limited data are available concerning peptide receptor radionuclide therapy (PRRT) of grade 3 (G3) neuroendocrine neoplasms (NENs) with a Ki-67 proliferation index of >20%. The purpose of this study was to analyze the long-term outcome, efficacy and safety of PRRT in patients with SSTR-expressing G3 NEN. A total of 69 patients (M=41 males; age 28-81 years) received PRRT with lutetium-177 (Lu) and/or yttium-90 (Y) labeled somatostatin analogs (DOTATATE or DOTATOC). Twenty-two patients had radiosensitising chemotherapy. Kaplan-Meier analysis was performed to calculate progression-free survival (PFS) and overall survival (OS), defined from start of PRRT, including a subgroup analysis for patients with a Ki-67 of ≤55% and >55%. Treatment response was evaluated according to RECIST 1.1 as well as by molecular imaging criteria (EORTC). Short and long-term toxicity was documented (CTCAE v.5.0) using a structured database (comprising over 250 items per patient) and retrospectively analyzed. Forty-six patients had pancreatic, 11 CUP, 6 midgut, 3gastric, and 3 rectal NEN. Median follow-up was 94.3 months. The median PFS was 9.6 months and median OS was 19.9 months. For G3 NEN with a Ki-67 ≤55% ( = 53), the median PFS was 11 months and median OS 22 months. Patients with a Ki-67 >55% ( = 11), had a median PFS of 4 months and a median OS of 7 months. For those patients with positive SSTR imaging, but no FDG uptake, the median PFS was 24 months and median OS was 42 months. A significant difference was found for both, PFS and OS, with a median PFS of 16 vs 5 months and a median OS of 27 vs 9 months for a SUV >15.0 and a SUV ≤15.0 on SSTR-PET, respectively. In the group with FDG scored as 3-4, the median PFS was 7.1 months and the median OS 17.2 months. For FDG scored as 0-2, the median PFS was 24.3 months and the median OS 41.6 months. PRRT was well-tolerated by all patients; no grade 3 or grade 4 hematotoxicity occurred and no clinically significant decline in renal function was observed. There was no hepatotoxicity. PRRT was tolerated well without significant adverse effects and is efficacious in G3 NEN with promising clinical outcome, especially in patients with a Ki-67 index of ≤55% and even in patients who have failed chemotherapy. Baseline FDG along with SSTR molecular imaging is useful to stratify those G3-NEN patients with high uptake on SSTR PET/CT and no or minor FDG-avidity, a mismatch pattern which is associated with a better long term prognosis.

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“…Recently, we developed a new class of small molecule albumin binding entities based on the long-circulating EB. EB displays a strong noncovalent binding with both murine and human serum albumin 37 - 40 . In our previous work, we have extensively studied the albumin binding abilities of EB conjugates with various chemical agents, and have confirmed their strong binding abilities 41 , 42 .…”

Section: Discussionmentioning

confidence: 99%

A paclitaxel prodrug with bifunctional folate and albumin binding moieties for both passive and active targeted cancer therapy

Shan¹,

Xin²,

Zhang³

et al. 2018

Theranostics

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Folate receptor (FR) has proven to be a valuable target for chemotherapy using folic acid (FA) conjugates. However, FA-conjugated chemotherapeutics still have low therapeutic efficacy accompanied with side effects, resulting from complications such as short circulation half-life, limited tumor delivery, as well as high kidney accumulation. Herein, we present a novel FA-conjugated paclitaxel (PTX) prodrug which was additionally conjugated with an Evans blue (EB) derivative for albumin binding. The resulting bifunctional prodrug prolonged blood circulation, enhanced tumor accumulation, and consequently improved tumor therapeutic efficacy.Methods: Fmoc-Cys(Trt)-OH was coupled onto PTX at the 7'-OH position for further synthesis of ester prodrug FA-PTX-EB. The targeting ability was investigated using confocal microscopy and flow cytometry. The pharmacokinetics of this bifunctional compound was also studied. Meanwhile, cell viability was evaluated in normal cells and three cancer cell lines by MTT assay. In vivo therapeutic effect was tested on FR-α overexpressing MDA-MB-231 tumor model.Results: Compared with free PTX, the FA-PTX, PTX-EB and FA-PTX-EB prodrugs increased circulation half-life in mice from 2.19 to 3.82, 4.41, and 7.51 h, respectively. Pharmacokinetics studies showed that the FA-PTX-EB delivered more PTX to tumors than FA-PTX and free PTX. In vitro and in vivo studies demonstrated that FA-EB-conjugated PTX induced potent antitumor activity.Conclusion: FA-PTX-EB showed prolonged blood circulation, enhanced drug accumulation in tumors, higher therapeutic index, and lower side effects than either free PTX or monofunctional FA-PTX and EB-PTX. The results support the potential of using EB for the development of long-acting therapeutics.

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“Albumin Hitchhiking” with an Evans Blue Analog for Cancer Theranostics

Cited by 22 publications

References 15 publications

Multidisciplinary Approaches Identify Compounds that Bind to Human ACE2 or SARS-CoV-2 Spike Protein as Candidates to Block SARS-CoV-2–ACE2 Receptor Interactions

Multidisciplinary Approaches Identify Compounds that Bind to Human ACE2 or SARS-CoV-2 Spike Protein as Candidates to Block SARS-CoV-2–ACE2 Receptor Interactions

Peptide Receptor Radionuclide Therapy in Grade 3 Neuroendocrine Neoplasms: Safety and Survival Analysis in 69 Patients

A paclitaxel prodrug with bifunctional folate and albumin binding moieties for both passive and active targeted cancer therapy

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