Cristina Espinosa Garcı́a

Midatech Pharma (United Kingdom)

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Tom Coulter

Midatech Pharma (United Kingdom)

Alessandro Pace

Midatech Pharma (United Kingdom)

Angela Byun Robinson

Cleveland Clinic

Sarah Hale

Midatech Pharma (United Kingdom)

Richard D. Perrins

Midatech Pharma (United Kingdom)

Philip M. Williams

University of Nottingham

Ketan Patel

St. John's University

Ibon Perera

Midatech Pharma (United Kingdom)

ÁG

África G. Barrientos

Midatech Pharma (United Kingdom)

U Aguilera Peral

Midatech Pharma (United Kingdom)

Cooperative Institutions

Midatech Pharma (United Kingdom)

University of Lincoln

University of Oxford

John Radcliffe Hospital

The Open University

Medical Research Council

Cancer Research UK

MRC Weatherall Institute of Molecular Medicine

Hungarian Academy of Sciences

Institute of Genetics

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

Bioconjugate Chemistry (2018)

Sarah Hale Richard D. Perrins Cristina Espinosa Garcı́a Alessandro Pace U Aguilera Peral

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 ∼3-fold 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.

Tolerability

Liver Cancer

Cabozantinib

10.1021/acs.bioconjchem.8b00873

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Citations (29)

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

Journal of Physics Conference Series (2017)

Meike Roskamp Tom Coulter Yao Ding Richard D. Perrins Cristina Espinosa Garcı́a

Ultra-small glycan-passivated gold nanoparticles of <2nm diameter were funtionalised with a short HS-EG(8)-COOH ligand. The nanoparticles were subsequently labelled, in a stoichiometrically controllable manner, with integrin-binding peptide SIKVAV and the maytansinoid cytotoxin DM4. In vitro assays showed significantly increased integrin-mediated uptake of SIKVAV labelled nanoparticles in HepG2 cells. SIKVAV targeted nanoparticle binding was shown to be outcompeted with free SIKVAV peptide, indicating target specific uptake. DM4 was passively attached to nanoparticles via sulfhydryl ligand exchange at the gold nanoparticle surface, which rendered them highly cytotoxic (IC50 ∼1 × 10−9M). In a rat model, pharmacokinetic studies showed that nanoparticle biodistribution was strongly altered by labelling with either peptide and DM4 moieties.

Biodistribution

IC50

10.1088/1742-6596/829/1/012017

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Galactose:PEGamine coated gold nanoparticles adhere to filopodia and cause extrinsic apoptosis

Nanoscale Advances (2018)

Konstantina Tzelepi Cristina Espinosa Garcı́a Philip M. Williams Jon P. Golding

Ultra-small gold nanoparticles, surface functionalised with a 50 : 50 ratio of a thiolated α-galactose derivative and a thiolated hexaethylene glycol amine, are toxic to HSC-3 oral squamous carcinoma cells. Differences in nanoparticle toxicity were found to be related to the synthesis duration, with 1 h reaction nanoparticles being less toxic than 5 h reaction nanoparticles. The ligand density decreased with longer reaction time, although the size, charge and ligand ratio remained similar. The concentration of sodium borohydride in the reaction decreased logarithmically over 5 h but remained within a concentration range sufficient to desorb weakly bound ligands, possibly explaining the observed gradual decrease in ligand density. Nanoparticle toxicity was abrogated by inhibition of either caspase 3/7 or caspase 8, but not by inhibition of caspase 9, consistent with extrinsic apoptosis. Electron microscopic analysis of cellular uptake demonstrated predominantly cytoplasmic localization. However, when energy-dependent transport was inhibited, by lowering the temperature to 4 °C, a remarkable adhesion of nanoparticles to filopodia was observed. Inhibition of filopodial assembly with a fascin inhibitor prevented nanoparticle adhesion to HSC-3 cells at 4 °C, while fascin inhibition at 37 °C resulted in less cytoplasmic uptake. More adhesion to HSC-3 filopodia was seen with the higher toxicity 5 h reaction time nanoparticles than with the 1 h nanoparticles. By including two further cell types (HaCaT keratinocytes and hCMEC/D3 endothelial cells), a pattern of increasing toxicity with filopodial binding of 5 h reaction nanoparticles became apparent.

Filopodia

10.1039/c8na00270c

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

Nanomaterials (2022)

Richard D. Perrins Lee-Anne McCarthy Angela Byun Robinson Kelly L. Spry Valentin Cognet

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.

Internalization

10.3390/nano12224013

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Citations (7)