Fab-conjugated PLGA nanoparticles effectively target cancer cells expressing human CD44v6

Acta Biomater. 2018 Nov:81:208-218. doi: 10.1016/j.actbio.2018.09.043. Epub 2018 Sep 27.

Abstract

Targeting of CD44 isoforms containing exon v6 (CD44v6) represents a viable strategy for the therapy and/or early diagnosis of metastatic cancers of the epithelium (e.g. gastric and colorectal cancer). We developed and characterized poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) modified with polyethylene glycol (PEG) and engrafted, by site-directed conjugation, with an engineered human Fab that specifically target human CD44v6 (v6 Fab-PLGA NPs). The v6 Fab-PLGA NPs displayed spherical morphology around 300 nm and were negatively charged. They strongly bound to a CD44v6-derived peptide and, more importantly, to cells that endogenously and exogenously express CD44v6, but not to non-expressing cells and cells expressing the standard isoform of CD44. The v6 Fab-PLGA NPs also recognized CD44v6 in tumor sections from cells grown subcutaneously within mice. The NPs had nominal cytotoxicity at 50 µg/mL and withstood simulated intestinal fluid exposure. Interestingly, v6 Fab-PLGA NPs cryopreserved in 10% trehalose and stored maintained specific cell binding. In conclusion, we envision NPs targeting CD44v6 as potential in vivo diagnostic agents and/or as anti-cancer agents in patients previously stratified with CD44v6+ carcinomas. STATEMENT OF SIGNIFICANCE: The v6 Fab-PLGA NPs displayed many favorable qualities as a potential CD44v6-targeted drug and/or diagnostic delivery agent. The NPs were designed for optimal ligand orientation and for immediate administration into humans. v6 Fab-PLGA NPs strongly bound to cells that endogenously and exogenously express CD44v6, but not to non-expressing cells and cells expressing the standard isoform of CD44. Binding ability was retained after freeze-drying and long-term storage, providing evidences on the stability of Fab-functionalized NPs. These NPs can potentially be used as an in vivo diagnostic from parenteral or oral/rectal administration.

Keywords: Antibody-conjugated nanoparticles; Human CD44v6; PLGA nanoparticles; Targeted drug delivery; Theranostics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cytotoxins* / chemistry
  • Cytotoxins* / pharmacokinetics
  • Cytotoxins* / pharmacology
  • Drug Carriers* / chemistry
  • Drug Carriers* / pharmacokinetics
  • Drug Carriers* / pharmacology
  • Humans
  • Hyaluronan Receptors / biosynthesis*
  • Nanoparticles
  • Neoplasm Proteins / biosynthesis*
  • Neoplasms* / drug therapy
  • Neoplasms* / metabolism
  • Neoplasms* / pathology
  • Polyglycolic Acid* / chemistry
  • Polyglycolic Acid* / pharmacokinetics
  • Polyglycolic Acid* / pharmacology

Substances

  • CD44v6 antigen
  • Cytotoxins
  • Drug Carriers
  • Hyaluronan Receptors
  • Neoplasm Proteins
  • Polyglycolic Acid