Near-infrared light-triggered prodrug photolysis by one-step energy transfer.

Prodrug photolysis enables spatiotemporal control of drug release at the desired lesions. For photoactivated therapy, near-infrared (NIR) light is preferable due to its deep tissue penetration and low phototoxicity. However, most of the photocleavable groups cannot be directly activated by NIR light. Here, we report a upconversion-like process via only one step of energy transfer for NIR light-triggered prodrug photolysis. We utilize a photosensitizer (PS) that can be activated via singlet-triplet (S-T) absorption and achieve photolysis of boron-dipyrromethene (BODIPY)-based prodrugs via triplet-triplet energy transfer. Using the strategy, NIR light can achieve green light-responsive photolysis with a single-photon process. A wide range of drugs and bioactive molecules are designed and demonstrated to be released under low-irradiance NIR light (100 mW/cm2, 5 min) with high yields (up to 87%). Moreover, a micellar nanosystem encapsulating both PS and prodrug is developed to demonstrate the practicality of our strategy in normoxia aqueous environment for cancer therapy. This study may advance the development of photocleavable prodrugs and photoresponsive drug delivery systems for photo-activated therapy.

Photoresponsive prodrug-dye nanoassembly for in-situ monitorable cancer therapy.

Photocleavable prodrugs enable controllable drug delivery to target sites modulated by light irradiation. However, the in vivo utility is usually hindered by their insolubility and inefficient delivery. In this study, we report a simple strategy of co-assembling boron-dipyrromethene-chlorambucil prodrug and near-infrared dye IR783 to fabricate photoresponsive nanoassemblies, which achieved both high prodrug loading capacity (~99%) and efficient light-triggered prodrug activation. The incorporated IR783 dye not only stabilized the nanoparticles and contributed tumor targeting as usual, but also exhibited degradation after light irradiation and in-situ monitoring of nanoparticle dissociation by fluorescent imaging. Systemic administration of the nanoparticles and localized light irradiation at tumor sites enabled monitorable and efficient drug release in vivo. Our results demonstrate that such prodrug-dye co-assembled nanomedicine is a promising formulation for photoresponsive drug delivery, which would advance the translation of photoresponsive nanomedicines.

Optochemical Control of mTOR Signaling and mTOR-Dependent Autophagy.

As an important regulator of cell metabolism, proliferation, and survival, mTOR (mammalian target of rapamycin) signaling provides both a potential target for cancer treatment and a research tool for investigation of cell metabolism. One inhibitor for both mTORC1 and mTORC2 pathways, OSI-027, exhibited robust anticancer efficacy but induced side effects. Herein, we designed a photoactivatable OSI-027 prodrug, which allowed the release of OSI-027 after light irradiation to inhibit the mTOR signaling pathway, triggering autophagy and leading to cell death. This photoactivatable prodrug can provide novel strategies for mTOR-targeting cancer therapy and act as a new tool for investigating mTOR signaling and its related biological processes.

One-photon red light-triggered disassembly of small-molecule nanoparticles for drug delivery.

BACKGROUND: Photoresponsive drug delivery can achieve spatiotemporal control of drug accumulation at desired sites. Long-wavelength light is preferable owing to its deep tissue penetration and low toxicity. One-photon upconversion-like photolysis via triplet-triplet energy transfer (TTET) between photosensitizer and photoresponsive group enables the use of long-wavelength light to activate short-wavelength light-responsive groups. However, such process requires oxygen-free environment to achieve efficient photolysis due to the oxygen quenching of triplet excited states. RESULTS: Herein, we report a strategy that uses red light to trigger disassembly of small-molecule nanoparticles by one-photon upconversion-like photolysis for cancer therapy. A photocleavable trigonal molecule, BTAEA, self-assembled into nanoparticles and enclosed photosensitizer, PtTPBP. Such nanoparticles protected TTET-based photolysis from oxygen quenching in normoxia aqueous solutions, resulting in efficient red light-triggered BTAEA cleavage, dissociation of nanoparticles and subsequent cargo release. With paclitaxel as the model drug, the red light-triggered drug release system demonstrated promising anti-tumor efficacy both in vitro and in vivo. CONCLUSIONS: This study provides a practical reference for constructing photoresponsive nanocarriers based on the one-photon upconversion-like photolysis.

Green Light-Triggered Intraocular Drug Release for Intravenous Chemotherapy of Retinoblastoma.

Retinoblastoma is one of the most severe ocular diseases, of which current chemotherapy is limited to the repetitive intravitreal injections of chemotherapeutics. Systemic drug administration is a less invasive route; however, it is also less efficient for ocular drug delivery because of the existence of blood-retinal barrier and systemic side effects. Here, a photoresponsive drug release system is reported, which is self-assembled from photocleavable trigonal small molecules, to achieve light-triggered intraocular drug accumulation. After intravenous injection of drug-loaded nanocarriers, green light can trigger the disassembly of the nanocarriers in retinal blood vessels, which leads to intraocular drug release and accumulation to suppress retinoblastoma growth. This proof-of-concept study would advance the development of light-triggered drug release systems for the intravenous treatment of eye diseases.

A Red Light-Triggered Drug Release System Based on One-Photon Upconversion-Like Photolysis.

Photoresponsive drug release systems can enhance drug accumulation at the sites where light is applied. Nowadays, the photocleavable groups used in the systems usually require ultraviolet or blue light irradiation, which limits tissue penetration depth and is harmful to normal cells and living bodies. A one-photon upconversion-like photolysis strategy, which can cleave green light-activatable prodrugs with red light at the presence of a red light-excitable photosensitizer in organic solvents, is developed. However, both the prodrug and photosensitizer are hydrophobic and their energy transfer process is sensitive to oxygen molecules. Here, a simple strategy to address these problems by loading the two components in biocompatible and biodegradable polymeric micelles, is presented. The developed low-irradiance red light-triggered drug release system has a size around 40 nm and exhibits good stability in aqueous solutions. The micellar encapsulation protects the photolysis reaction from oxygen quenching in normoxia aqueous solutions. The therapeutic effect of the system enhanced by the redlight irradiation is demonstrated through in vitro and in vivo studies, indicating promising potential in cancer therapy. The study provides the first example and also an important reference for applying one-photon upconversion-like photolysis in biomedical applications.