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

Abstract

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.

Harmonic generation at the nanoscale

“…In a first embodiment, the SHG emission from BaTiO 3 HNPs upon irradiation at 1040 nm resulted in the excitation of nearby photosensitizers (rose Bengal) used in photodynamic therapy [Sun et al (2019)]. In a second setting, the SHG emitted by Bismuth Ferrite nanoparticles was used as a stimulus to trigger the photo-uncaging of a molecular cargo (tryptophan) [Vuilleumier et al (2019)] (see Fig. 6c).…”

Photocontrolled Release of the Anticancer Drug Chlorambucil with Caged Harmonic Nanoparticles

“…Based on the protocol that we previously established for the NIR‐triggered release of model molecular cargo from BFO HNPs, the uncaging of Clb from LNO‐APTES‐CM‐Clb NPs was investigated using a Ti:Sapphire pulsed laser system ( Figure ,A ). Upon femtosecond excitation at 800 nm, the emission spectrum of LNO‐APTES‐CM‐Clb NPs in Figure ,B , obtained by averaging the response from large field‐of‐view multiphoton multispectral images, reveals a sharp peak at short wavelength corresponding to the second harmonic signal of the HNPs and a broad luminescence emission resulting from the CM moiety.…”

“…Very recently, we demonstrated, for the first time, that the harmonic emission of BFO HNPs can be used as a local efficient trigger for the controlled release of l ‐tryptophan from caged coumarin (CM)‐based derivatives conjugated to the NP surface . Herein, we present the development of this methodology for the two‐photon‐triggered release of the anticancer drug chlorambucil (Clb) from caged LNO HNPs, offering the possibility to reduce its non‐specific cytotoxicity by on‐demand light‐activated delivery.…”

Lighting the Path: Light Delivery Strategies to Activate Photoresponsive Biomaterials In Vivo

“…Bismuth ferrate (BiFeO 3 , BFO) and lithium niobate (LiNbO 3 , NLO) are particular standouts that show high SHG efficiency [ 72 ] and low cytotoxicity. [ 73 ] Demonstrations of L‐tryptophan and anticancer drug chlorambucin release from LNO particles by cleavage of curcumin linkers have provided a glimpse of in vivo potential, [ 74 ] but the in vitro irradiation conditions of E pulse = 300 GW cm −2 (790 nm, 50 fs pulses, 1 kHz repetition rate, E average = 15 W cm −2 ) required 25 min for 80% release, with a significant proportion of this release occurring through 2P activation despite the photocleavable groups not being optimized for 2P absorption. [ 74b ] An SHG‐driven model photoreaction therefore proceeds with comparable efficiency to a 2P photoactivation, as illustrated in Figure 3e, and is accompanied by the same hardware requirements (pulsed laser, complicated optics) that hamper in vivo adoption.…”

“…[ 73 ] Demonstrations of L‐tryptophan and anticancer drug chlorambucin release from LNO particles by cleavage of curcumin linkers have provided a glimpse of in vivo potential, [ 74 ] but the in vitro irradiation conditions of E pulse = 300 GW cm −2 (790 nm, 50 fs pulses, 1 kHz repetition rate, E average = 15 W cm −2 ) required 25 min for 80% release, with a significant proportion of this release occurring through 2P activation despite the photocleavable groups not being optimized for 2P absorption. [ 74b ] An SHG‐driven model photoreaction therefore proceeds with comparable efficiency to a 2P photoactivation, as illustrated in Figure 3e, and is accompanied by the same hardware requirements (pulsed laser, complicated optics) that hamper in vivo adoption. UCNPs can efficiently convert long wavelength photons to short wavelength ones at much lower irradiances, but the lossless nature of SHG accompanied by its wavelength independence may encourage further developments in vivo especially as more efficient, cytocompatible “harmophores” are developed.…”