title: Cathepsin B-degradable, NIR-responsive nanoparticulate platform for target-specific cancer therapy.
abstract: Stimuli-responsive anticancer formulations can promote drug release and activation within the target tumour, facilitate cellular uptake, as well as improve the therapeutic efficacy of drugs and reduce off-target effects. In the present work, indocyanine green (ICG)-containing polyglutamate (PGA) nanoparticles were developed and characterized. Digestion of nanoparticles with cathepsin B, a matrix metalloproteinase overexpressed in the microenvironment of advanced tumours, decreased particle size and increased ICG cellular uptake. Incorporation of ICG in PGA nanoparticles provided the NIR-absorbing agent with time-dependent altered optical properties in the presence of cathepsin B. Having minimal dark toxicity, the formulation exhibited significant cytotoxicity upon NIR exposure. Combined use of the formulation with saporin, a ribosome-inactivating protein, resulted in synergistically enhanced cytotoxicity attributed to the photo-induced release of saporin from endo/lysosomes. The results suggest that this therapeutic approach can offer significant therapeutic benefit in the treatment of superficial malignancies, such as head and neck tumours.
authors.affiliation: Division of Surgery & Interventional Science, University College London, Royal Free Hospital, Pond Street, NW3 2PF, London, UK.
authors.forename: Sam P
authors.initials: SP
authors.lastname: Tarassoli
authors.forename: Alejandra Martinez
authors.initials: AM
authors.lastname: de Pinillos Bayona
authors.forename: Hayley
authors.initials: H
authors.lastname: Pye
authors.forename: C Alexander
authors.initials: CA
authors.lastname: Mosse
authors.forename: John F
authors.initials: JF
authors.lastname: Callan
authors.forename: Alexander
authors.initials: A
authors.lastname: MacRobert
authors.forename: Anthony P
authors.initials: AP
authors.lastname: McHale
authors.forename: Nikolitsa
authors.initials: N
authors.lastname: Nomikou
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D002401:Cathepsin B / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004396:Coloring Agents / Q000737:chemistry; D004339:Drug Compounding / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods*; D065546:Drug Liberation; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D006801:Humans; D007208:Indocyanine Green / Q000737:chemistry; D007259:Infrared Rays; D007700:Kinetics; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D058990:Molecular Targeted Therapy / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D011099:Polyglutamic Acid / Q000737:chemistry; D059748:Proteolysis; D054789:Ribosome Inactivating Proteins, Type 1 / Q000737:chemistry / Q000494:pharmacology*; D000076985:Saporins
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D054789:Ribosome Inactivating Proteins, Type 1; D011099:Polyglutamic Acid; D000076985:Saporins; D002401:Cathepsin B; D007208:Indocyanine Green