Repurposing of Cetuximab in antibody-directed chemotherapy-loaded nanoparticles in EGFR therapy-resistant pancreatic tumours

McDaid, William J.; Greene, Michelle K.; Johnston, Michael C.; Pollheimer, Ellen; Smyth, Peter; McLaughlin, Kylie A.; Schaeybroeck, Sandra Van; Straubinger, Robert M.; Longley, Daniel B.; Scott, Christopher J.

doi:10.1039/c9nr07257h

Cited by 45 publications

(22 citation statements)

References 42 publications

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“…Another receptor widely used to perform active uptake in cancer cells is the epidermal growth factor receptor (EGFR). As reported by McDaid et al (2019), the functionalization of PLGA NPs surface by using a therapeutic mAb against EGFR (Cetuximab) enhanced the NPs uptake in an in vivo model. A further example of mAb modified NPs to improve cellular internalization was reported by Khanna et al (2019), where PLGA nanoparticles were functionalized with a mAb against heparan sulfate proteoglycan 2 (HSPG2) protein, a surface receptor highly expressed in triple negative breast cancer (TNBC) that binds growth factors such as VEGF-A and FGF-2, acting as "co-receptor."…”

Section: Active Uptakementioning

confidence: 63%

Nanoparticle Surface Functionalization: How to Improve Biocompatibility and Cellular Internalization

Sanità

Carrese

Lamberti

2020

Front. Mol. Biosci.

375

147

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The use of nanoparticles (NP) in diagnosis and treatment of many human diseases, including cancer, is of increasing interest. However, cytotoxic effects of NPs on cells and the uptake efficiency significantly limit their use in clinical practice. The physico-chemical properties of NPs including surface composition, superficial charge, size and shape are considered the key factors that affect the biocompatibility and uptake efficiency of these nanoplatforms. Thanks to the possibility of modifying physico-chemical properties of NPs, it is possible to improve their biocompatibility and uptake efficiency through the functionalization of the NP surface. In this review, we summarize some of the most recent studies in which NP surface modification enhances biocompatibility and uptake. Furthermore, the most used techniques used to assess biocompatibility and uptake are also reported.

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Section: Active Uptakementioning

confidence: 63%

Nanoparticle Surface Functionalization: How to Improve Biocompatibility and Cellular Internalization

Sanità

Carrese

Lamberti

2020

Front. Mol. Biosci.

375

147

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“…Mutations of receptors and the components in the signaling pathway may decrease the efficacy of antibody-targeted therapy. If cells express a variant of the receptor, therapy's potency may still decrease even if the binding site does not change [46].…”

Section: Resistance To Mabmentioning

confidence: 99%

Targeted Cancer Therapy Using Nanoparticles and Antibody Fragments

Bhattacharya¹,

Gore²

2021

Advances in Precision Medicine Oncology

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Cancer is caused by an uncontrolled cell division, forming a tumor capable of metastasis. Cancer is the second leading cause of death worldwide. Conventional treatments kill healthy cells, causing side effects. Recently, nanomaterials are explored due to properties such as as- nano-size, high loading, and ligands’ attachment for a selective delivery. Apart from normal body cells, cancer cells express many receptors in excess, which serve as ‘targets’ for attacking the cells. Various ligands like proteins, peptides, polysaccharides can be attached to nanoparticles to allow proper and specific reach to the tumor. Such nanoparticles go to their desired site and stick onto the receptors, taken inside the cells by various methods. Antibodies are natural proteins that bind to foreign substances and remove them. IgG being the most explored antibody, suffers from many disadvantages such as non-specificity for required antigen, limited binding sites, low tumor penetration. Hence many researchers experimented by removing and adjusting the binding sites, using only the binding sites, enhancing the valency of naturally available IgG. It gave many benefits such as enhanced penetration, reduced immunogenicity, better delivery of drugs with fewer side effects. Continuing advancements in the field of protein engineering will help scientists to come up with better solutions. The properties allow easy surface interaction and entry, achieve better biodistribution, and reduce the amount of drug required. Targeting is based on Paul Ehrlich’s ‘magic bullet, ‘where the therapeutic moiety has two parts-one to identify the target and the second to eliminate it. This concept is revised to incorporate a third component, a carrier. Many nanocarriers can be used to target cancer cells containing ligands to identify malignant cells. Approaches to targeting are passive, active and physical targeting. Many such nanoparticles are in clinical trials and can be a better solution to cancer therapy.

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“…To date, numerous EGFR-targeted nanoparticles have been examined as drug delivery vehicles in the treatment of pancreatic cancer. 6,[35][36][37] However, most of these efforts have involved random bioconjugation of full antibody targeting ligands to the surface of nanoparticles, providing clear scope for further improvement that we wished to address. Thus, following the successful development and validation of native CTX F(ab) NP and modified CTX F(ab) NP [disulfide], their utility as a targeted drug delivery platform was next explored using the topoisomerase 1 inhibitor CPT as a model agent.…”

Section: Targeted Delivery Of Nanoformulated Cpt To Egfr-expressing Pmentioning

confidence: 99%

“…[1][2][3] However, reliance on passive targeting may not be sufficient to realise the full clinical application of chemotherapy-loaded nanoparticles, and so surface functionalisation with targeting ligands is an attractive approach to enhance cellular binding and uptake. 4 Despite a wealth of preclinical data supporting this conceptual approach, [5][6][7] none have successfully translated through to clinical approval.…”

Section: Introductionmentioning

confidence: 99%

Refined construction of antibody-targeted nanoparticles leads to superior antigen binding and enhanced delivery of an entrapped payload to pancreatic cancer cells

et al. 2020

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Repurposing of Cetuximab in antibody-directed chemotherapy-loaded nanoparticles in EGFR therapy-resistant pancreatic tumours

Abstract: The use of CTX as a targeting agent for camptothecin-loaded polymeric nanoparticles directed against KRAS mutant CTX-resistant cancer cells was investigated. CTX increased CPT internalisation into cancer cells resulting in elevated cancer cell death.

Cited by 45 publications

References 42 publications

Nanoparticle Surface Functionalization: How to Improve Biocompatibility and Cellular Internalization

Nanoparticle Surface Functionalization: How to Improve Biocompatibility and Cellular Internalization

Targeted Cancer Therapy Using Nanoparticles and Antibody Fragments

Refined construction of antibody-targeted nanoparticles leads to superior antigen binding and enhanced delivery of an entrapped payload to pancreatic cancer cells

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