SIKVAV peptide functionalized ultra-small gold nanoparticles for selective targeting of α6β1 integrin in hepatocellular carcinoma

Roskamp, Meike; Coulter, Tom; Ding, Yao; Perrins, Richard D.; Garcia, Cristina Espinosa; Pace, Alessandro; Hale, Sarah; Robinson, Angela Byun; Williams, Philip M.; Peral, Usoa; Patel, Ketan; Palmer, Daniel D.

doi:10.1088/1742-6596/829/1/012017

Cited by 4 publications

(6 citation statements)

References 29 publications

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“…In order to study the biological potential of ultrasmall gold nanoparticles as a drug vehicle for the treatment of hepatocellular carcinoma, 2 nm gold core particles were synthesized and passivated with carboxylic acid terminated polyethylene glycol thiol ligands and 1-(2-mercaptoethoxy)-α-galactose C 2 (αGalC 2 ) using a modified Brust-Schiffrin method as described previously. , The base particle (MTC-100011) was then functionalized with the potent maytansine analogue DM1, using Murry ligand exchange methodology, to generate MTC-100038 (annotated in Figure a). Methods to precisely evaluate the ligand composition of MTC-100038 are technically challenging and as such are still under development.…”

Section: Resultsmentioning

confidence: 99%

“…Analytical methods used for physicochemical characterization of GNPs have been described in detail previously elsewhere . Briefly, UV–vis absorption spectra were measured using a BMG Labtech SPECTROstar Nano microwell plate spectrophotometer.…”

Section: Methodsmentioning

confidence: 99%

“…Analytical methods used for physicochemical characterization of GNPs have been described in detail previously elsewhere. 37 Briefly, UV−vis absorption spectra were measured using a BMG Labtech SPECTROstar Nano microwell plate spectrophotometer. Dynamic light scattering (DLS) was measured in triplicate using a Zetasizer Nano ZSP (Malvern Instruments Ltd., UK), at 25°C in distilled water.…”

Section: ■ Experimental Methodsmentioning

confidence: 99%

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DM1 Loaded Ultrasmall Gold Nanoparticles Display Significant Efficacy and Improved Tolerability in Murine Models of Hepatocellular Carcinoma

Hale

Perrins

et al. 2018

Bioconjugate Chem.

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Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide with poor prognosis and limited options for treatment. Life expectancy after diagnosis is short; the currently available treatments are not well tolerated and have limited clinical benefit. There is a clear unmet clinical need for the development of new treatments. In this study, ultrasmall, 2 nm gold core nanoparticles (MidaCore) conjugated with the potent maytansine analogue DM1 (MTC-100038) were assessed as a systemic nanomedicine for the treatment of hepatocellular carcinoma. The platform improved overall tolerability of DM1, permitting ∼3fold higher levels of drug to be administered compared to free drug. Dose for dose, MTC-100038 also facilitated delivery of ∼2.0-fold higher (p = 0.039) levels of DM1 to the tumor compared to free DM1. MTC-100038 produced significant efficacy (tumor growth index ∼102%; p = <0.0001), in several murine xenograft models of HCC, and was superior to both free DM1 and the current standard of care, sorafenib. Furthermore, MTC-100038 displayed potent (nM) in vitro activity in various HCC primary patient derived cell lines and across various other different cancer cell types. These data demonstrate the potential of MidaCore nanoparticles to enhance tumor delivery of cytotoxic drugs and indicate MTC-100038 is worthy of further investigation as a potential treatment for HCC and other cancer types.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: ■ Experimental Methodsmentioning

confidence: 99%

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DM1 Loaded Ultrasmall Gold Nanoparticles Display Significant Efficacy and Improved Tolerability in Murine Models of Hepatocellular Carcinoma

Hale

Perrins

et al. 2018

Bioconjugate Chem.

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“…Two types of ligands were used in a 50:50 ratio to make base usGNPs: a monosaccharide with a short ethyl side chain 2 -Thioethyl α-D-galactopyranoside (α-Galactose-C 2 ) and an oligoethylene glycol α-Thio-ω-(propionic acid) octa(ethylene glycol) (PEG(8)COOH). Twonanometer core GNPs functionalized with the same mixed corona and the SIKVAV peptide have been previously demonstrated to have the ability to target cancer cells through α6β1 integrins [52]. A similar structure with a 2 nm core functionalized with cRGD and the same negatively charged oligoethylene glycol ligand also showed promising results in vitro [53].…”

Section: Synthesis and Characterization Of Functionalized Gold Nanopa...mentioning

confidence: 99%

Targeting Ultrasmall Gold Nanoparticles with cRGD Peptide Increases the Uptake and Efficacy of Cytotoxic Payload

et al. 2022

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Cyclic arginyl-glycyl-aspartic acid peptide (cRGD) peptides show a high affinity towards αVβ3 integrin, a receptor overexpressed in many cancers. We aimed to combine the versatility of ultrasmall gold nanoparticles (usGNP) with the target selectivity of cRGD peptide for the directed delivery of a cytotoxic payload in a novel design. usGNPs were synthesized with a modified Brust-Schiffrin method and functionalized via amide coupling and ligand exchange and their uptake, intracellular trafficking, and toxicity were characterized. Our cRGD functionalized usGNPs demonstrated increased cellular uptake by αVβ3 integrin expressing cells, are internalized via clathrin-dependent endocytosis, accumulated in the lysosomes, and when loaded with mertansine led to increased cytotoxicity. Targeting via cRGD functionalization provides a mechanism to improve the efficacy, tolerability, and retention of therapeutic GNPs.

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“…Even though RGD is the most sought-after ligand for integrin-mediated angiogenesis, a few other integrin-binding peptides have also been explored for similar purposes. The laminin-derived peptide sequence SIKVAV known to bind integrins α3β1 and α6β1 has been explored to design gold nanoparticles to enhance target-specific uptake [117]. Similar sequences when used to decorate a polymer-coated virus allowed tumor-specific uptake of the modified virus via α6 integrins [118].…”

Section: Is Rgd-mediated Targeting Good Enough?mentioning

confidence: 99%

Integrin-Mediated Delivery of Drugs and Nucleic Acids for Anti-Angiogenic Cancer Therapy: Current Landscape and Remaining Challenges

Majumder

2018

Bioengineering

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Angiogenesis, sprouting of new blood vessels from pre-existing vasculatures, plays a critical role in regulating tumor growth. Binding interactions between integrin, a heterodimeric transmembrane glycoprotein receptor, and its extracellular matrix (ECM) protein ligands govern the angiogenic potential of tumor endothelial cells. Integrin receptors are attractive targets in cancer therapy due to their overexpression on tumor endothelial cells, but not on quiescent blood vessels. These receptors are finding increasing applications in anti-angiogenic therapy via targeted delivery of chemotherapeutic drugs and nucleic acids to tumor vasculatures. The current article attempts to provide a retrospective account of the past developments, highlight important contemporary contributions and unresolved set-backs of this emerging field.

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SIKVAV peptide functionalized ultra-small gold nanoparticles for selective targeting of α6β1 integrin in hepatocellular carcinoma

Cited by 4 publications

References 29 publications

DM1 Loaded Ultrasmall Gold Nanoparticles Display Significant Efficacy and Improved Tolerability in Murine Models of Hepatocellular Carcinoma

DM1 Loaded Ultrasmall Gold Nanoparticles Display Significant Efficacy and Improved Tolerability in Murine Models of Hepatocellular Carcinoma

Targeting Ultrasmall Gold Nanoparticles with cRGD Peptide Increases the Uptake and Efficacy of Cytotoxic Payload

Integrin-Mediated Delivery of Drugs and Nucleic Acids for Anti-Angiogenic Cancer Therapy: Current Landscape and Remaining Challenges

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