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

• Published in: Nanoscale 2020-06, Vol.12 (21), p.11647-11658
• Main Authors: Greene, Michelle K, Nogueira, João C. F, Tracey, Shannon R, Richards, Daniel A, McDaid, William J, Burrows, James F, Campbell, Katrina, Longley, Daniel B, Chudasama, Vijay, Scott, Christopher J
• Format: Article
• Language: English
• Subjects: Alkynes; Antibodies; Antibodies - chemistry; Antibodies - metabolism; Antigens; Antigens, Neoplasm - metabolism; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Camptothecin - chemistry; Camptothecin - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Cetuximab - chemistry; Cetuximab - metabolism; Conjugation; Construction methods; Drug delivery systems; Drug Delivery Systems - methods; Entrapment; ErbB Receptors - metabolism; Growth factors; Humans; Immunoglobulin Fab Fragments - chemistry; Immunoglobulin Fab Fragments - metabolism; Manufacturability; Monoclonal antibodies; Nanoparticles; Nanoparticles - chemistry; Nanoparticles - metabolism; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Surface Properties; Targeted cancer therapy; Toxicity
• ISSN: 2040-3364; 2040-3372
• DOI: 10.1039/d0nr02387f

Antibody-targeted nanoparticles have shown exceptional promise as delivery vehicles for anticancer drugs, although manufacturability challenges have hampered clinical progress. These include the potential for uncontrolled and random antibody conjugation, resulting in masked or inactive paratopes and unwanted Fc domain interactions. To circumvent these issues, we show that the interchain disulfide of cetuximab F(ab) may be selectively re-bridged with a strained alkyne handle, to permit 'click' coupling to azide-capped nanoparticles in a highly uniform and oriented manner. When compared to conventional carbodiimide chemistry, this conjugation approach leads to the generation of nanoparticles with a higher surface loading of cetuximab F(ab) and with markedly improved ability to bind to the target epidermal growth factor receptor. Moreover, we show that entrapment of a camptothecin payload within these nanoparticles can enhance drug targeting to antigen-expressing pancreatic cancer cells, resulting in superior cytotoxicity versus the conventional nanoformulation. Collectively, this work highlights the critical need to develop refined methods for the construction of targeted nanoparticles that will accelerate their clinical translation through improved performance and manufacturability. We outline a facile approach for the highly controlled and oriented coupling of antibody fragments to nanoparticles. We demonstrate the superior performance of these nanoparticles as targeted drug delivery vehicles versus a conventional formulation.