Two-Photon-Triggered Photorelease of Caged Compounds from Multifunctional Harmonic Nanoparticles.

The design of stimuli-responsive nanocarriers has raised much attention to achieve higher local concentration of therapeutics and mitigate the appearance of drug resistance. The combination of imaging properties and controlled photorelease of active molecules within the same nanoconjugate has a great potential for theranostic applications. In this study, a system for NIR light-triggered release of molecular cargos induced by the second harmonic emission from bismuth ferrite harmonic nanoparticles (BFO HNPs) is presented. Silica-coated BFO HNPs were covalently conjugated to a photocaging tether based on coumarin (CM) and l-tryptophan (Trp) as a model molecular cargo. Upon femtosecond pulsed irradiation at 790 nm, Trp was efficiently released from the NP surface in response to the harmonic emission of the nanomaterial at 395 nm. The emitted signal induced the photocleavage of the CM-Trp carbamate linkage resulting in the release of Trp, which was monitored and quantified by ultrahigh performance liquid chromatography-mass spectrometry (UHPLC-MS). While a small fraction of the uncaging process could be attributed to the nonlinear absorption of CM derivatives, the main trigger responsible for Trp release was established as the second harmonic signal from BFO HNPs. This strategy may provide a new way for the application of functionalized HNPs in dual imaging delivery theranostic protocols.

Inhibitor-conjugated harmonic nanoparticles targeting fibroblast activation protein.

The recent progress in the engineering of nanosized inorganic materials presenting tailored physical properties and reactive surface for post-functionalization has opened promising avenues for the use of nanoparticles (NPs) in diagnosis and therapeutic intervention. Surface decoration of metal oxide NPs with ligands modulating circulation time, cellular uptake, affinity and extravasation through active targeting led to efficient cancer specific bioimaging probes. The most relevant cancer biomarkers studied so far include surface and transmembrane cancer cell receptors. More recently, tumor microenvironments and more specifically the fibroblastic element of the tumor stroma have emerged as a valuable target for diagnosis and treatment of several types of cancers. In this study, a low molecular weight ligand targeting fibroblast activation protein α (FAP), which is specifically expressed by activated fibroblasts of the tumor stroma, was synthesized. This ligand demonstrated nanomolar inhibition of FAP with high selectivity with respect to prolyl oligopeptidase (PREP) and dipeptidyl peptidase (DPP) IV, as well as good biocompatibility toward a human lung tissue model. Bismuth ferrite (BFO) harmonic nanoparticles (HNPs) conjugated to this ligand showed target-specific association to FAP as demonstrated by reverse ELISA-type assay using Human Fibroblast Activation Protein alpha/FAP Alexa Fluor® 594-conjugated Antibody and multiphoton multispectral microscopy experiments. These functionalized HNPs may provide new nanocarriers to explore the role of FAP in tumorigenesis and to target the fibroblastic component of the tumor microenvironment.