facile-preparation-and-photoactivation-of-prodrug-dye-nanoassemblies

Facile Preparation and Photoactivation of Prodrug-Dye Nanoassemblies

Self-assembly is a simple yet reliable method for constructing nanoscale drug delivery systems. Photoactivatable prodrugs enable controllable drug release ...

The University of Hong Kong

Carvedilol (CAR), a β-adrenoceptor and α1-receptor blocker, has pH-dependent solubility, which greatly limits its oral bioavailability. In this work, a precipitation inhibitor-based self-nanoemulsifying drug delivery system (PI-SNEDDS) was developed by employing Soluplus and Poloxamer 407 to improve drug dissolution and to inhibit drug precipitation in the gastrointestinal tract. In vitro phase distribution and in vivo dissolution studies indicated that PI-SNEDDS significantly increased drug content in the oil phase of the nanoemulsions in the stomach and greatly inhibited the subsequent precipitation of CAR in the intestine compared with the carvedilol self-nanoemulsifying drug delivery system (CAR SNEDDS) and the carvedilol tablets. Moreover, a 1.56-fold increase in the relative bioavailability of CAR was observed for the CAR PI-SNEDDS (397.41%) compared to a CAR SNEDDS (254.09%) with commercial capsules as a reference. Therefore, our developed PI-SNEDDS is a promising vehicle for improving the dissolution and bioavailability of poorly soluble drugs with pH-dependent solubility.

A Soluplus/Poloxamer 407-based self-nanoemulsifying drug delivery system for the weakly basic drug carvedilol to improve its bioavailability.

Trigonal molecules have a special triskelion structure similar to clathrin protein, providing great inspiration for constructing artificial nanoassemblies. To date, various synthetic trigonal conjugates have been designed for supramolecular self-assembly, which have demonstrated versatile and controllable self-assembly ability in materials science. Here we will review the design of trigonal (sometimes called three-legged, tripodal, C3-symmetric, or triskelion) building blocks that can self-assemble into various nanostructures and discuss the biomedical applications of the self-assembled nanomaterials.

Self-assembly of trigonal building blocks into nanostructures: molecular design and biomedical applications.

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.

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

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.

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

Numerous recently developed therapies have highlighted the advantages of using proteins as therapeutics. However, in many protein delivery systems, the complicated carrier designs, low loading content, and off-targeting effects have limited their clinical applications. Here we report a photoresponsive protein-binding moiety and use it to prepare a simple nanoscale protein delivery system with high delivery efficiency and photoenhanced cellular uptake of proteins. The carrier was prepared by modifying a photocleavable molecule, DEACM, onto the surface of a cationic dendrimer, poly(amidoamine). DEACM simultaneously contributed to protein binding, self-assembly, and photocontrollability of the system. The multi-functional DEACM enabled the simplicity of the protein delivery system, which does not require complex organic synthesis or protein modification. The high delivery efficiency, high serum tolerance, and photoenhanced cellular uptake have been proved with functional proteins, presenting the potential for delivering protein therapeutics.

Photoenhanced cytosolic protein delivery based on a photocleavable group-modified dendrimer.

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.

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

Quantitative drug release is important for improving therapeutic efficiency and avoiding side effects. While using long-term delivery system for repeated therapies, it is indispensable but challenging to accurately control the drug dosing. Here, a photocleavable prodrug loaded hydrogel is proposed for near infrared (NIR) light-triggered quantitative pulsed drug release. IR783, a commercially available NIR fluorescent dye, is conjugated with methyl honokiol (mHNK) to give a photocleavable IR783-mHNK prodrug. Injectable glycol chitosan (GC) hydrogel is chosen as a reservoir, in which IR783-mHNK can be efficiently loaded via electrostatic and hydrophobic interactions. Upon 680 nm light-emitting diode (LED) light irradiation, IR783-mHNK cleaves and mHNK is released. Notably, it is found that IR783-mHNK presents synchronous photocleavage-fluorescence bleaching phenomenon. The released amount of mHNK is visible by measuring the residual fluorescent intensity of hydrogel. Quantitative drug release is achieved by controlling irradiation duration and the drug release process is visible by fluorescence imaging. The prodrug-loaded hydrogel shows good stability, minimum leakage and efficient light responsibility both in vitro and in vivo. After light triggering, monitorable quantitative mHNK release and on-demand sleep-promotiing effect are verified in mice without toxicities.

NIR Light-Triggered Quantitative Pulsed Drug Release.

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.

Optochemical Control of mTOR Signaling and mTOR-Dependent Autophagy.

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.

Article	Year
A Soluplus/Poloxamer 407-based self-nanoemulsifying drug delivery system for the weakly basic drug carvedilol to improve its bioavailability. Nanomedicine : nanotechnology, biology, and medicine\| PubMed ID: 32275957	2020
Self-assembly of trigonal building blocks into nanostructures: molecular design and biomedical applications. Journal of materials chemistry. B\| PubMed ID: 32686806	2020
A Red Light-Triggered Drug Release System Based on One-Photon Upconversion-Like Photolysis. Advanced healthcare materials\| PubMed ID: 32985134	2020
Green Light-Triggered Intraocular Drug Release for Intravenous Chemotherapy of Retinoblastoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany)\| PubMed ID: 34448360	2021
Photoenhanced cytosolic protein delivery based on a photocleavable group-modified dendrimer. Nanoscale\| PubMed ID: 34668505	2021
One-photon red light-triggered disassembly of small-molecule nanoparticles for drug delivery. Journal of nanobiotechnology\| PubMed ID: 34736466	2021
NIR Light-Triggered Quantitative Pulsed Drug Release. Advanced healthcare materials\| PubMed ID: 34851048	2022
Optochemical Control of mTOR Signaling and mTOR-Dependent Autophagy. ACS pharmacology & translational science\| PubMed ID: 35311017	2022
Photoresponsive prodrug-dye nanoassembly for in-situ monitorable cancer therapy. Bioengineering & translational medicine\| PubMed ID: 36176605	2022

Kaiqi Long

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