阅读说明：本技术 采用长波长光激发的三重态-三重态能量转移及其方法 (Triplet-triplet energy transfer using long wavelength photoexcitation and methods therefor ) 是由 汪卫平 吕雯 于 2019-08-21 设计创作，主要内容包括：各种光触发药物释放和光反应领域,包括通常基于采用长波长光激发的三重态-三重态能量转移的反应。用于在光敏剂中吸收能量的系统和方法,以及用于制造或使用这样的系统的方法,包括这样的系统的试剂盒。所述系统和方法包括通过三重态-三重态能量转移来转移该能量以裂解可裂解的或其它活性部分,例如,从而引起可释放部分的释放。在一些情况下,这些可以包含在合适的载体材料,如颗粒或胶束中。这样的系统和方法可以用于各种应用,包括各种生物或物理应用。例如,这样的系统和方法可用于将药物或其它可释放部分递送至受试者的区域。(Various areas of photo-triggered drug release and photoreaction include reactions that are typically based on triplet-triplet energy transfer with long wavelength photoexcitation. Systems and methods for absorbing energy in a photosensitizer, and methods for making or using such systems, kits comprising such systems. The systems and methods include transferring this energy by triplet-triplet energy transfer to cleave a cleavable or other active moiety, e.g., to cause release of a releasable moiety. In some cases, these may be contained in a suitable carrier material, such as a particle or micelle. Such systems and methods may be used in a variety of applications, including various biological or physical applications. For example, such systems and methods may be used to deliver a drug or other releasable moiety to an area of a subject.)

1. A composition, comprising: a photosensitizer; a cleavable moiety that accepts a triplet-triplet energy transfer from a photosensitizer in a higher energy state to cause cleavage of the cleavable moiety; and a releasable moiety releasable from the composition upon cleavage of the cleavable moiety, wherein the composition does not comprise an annihilating agent.

2. The composition of claim 1, wherein the photosensitizer comprises a transition metal-porphyrin.

3. The composition of claim 2, wherein the photosensitizer comprises a Pt porphyrin.

4. The composition of claim 3, wherein the photosensitizer is platinum (II) tetraphenyl tetraphenylporphyrin (PtTPBP).

5. The composition of claim 1, wherein the photosensitizer has an excitation wavelength of from about 600nm to about 1200 nm.

6. The composition of claim 5, wherein the photosensitizer has an excitation wavelength of 600nm to about 700 nm.

7. The composition of claim 6, wherein the photosensitizer has an excitation wavelength of about 625 nm.

8. The composition of claim 1, wherein the cleavable moiety is photocleavable.

9. The composition of claim 8, wherein the cleavable moiety comprises a prodrug.

10. The composition of claim 9, wherein the prodrug comprises a drug linked to BODIPY.

11. The composition of claim 1, further comprising a carrier material.

12. The composition of claim 11, wherein the carrier material comprises the photosensitizer and the cleavable moiety.

13. The composition of claim 11, wherein the carrier material further comprises the releasable moiety.

14. The composition of claim 11, wherein the carrier material comprises a polymer.

15. The composition of claim 14, wherein the carrier material comprises particles.

16. The composition of claim 15, wherein the particles have an average diameter of less than about 1 mm.

17. The composition of claim 11, wherein the support material comprises a film.

18. The composition of claim 11, wherein the carrier material comprises a polymeric micelle.

19. The composition of claim 1, wherein the releasable moiety is a drug.

20. The composition of claim 1, wherein the releasable moiety is an anti-inflammatory drug, an anti-cancer drug, or an anti-angiogenic drug.

21. The composition of claim 1, wherein the releasable moiety is Chlorambucil (CAB).

22. A composition, comprising: a photosensitizer; an active moiety that accepts triplet-triplet energy transfer from a photosensitizer in a higher energy state to cause a chemical reaction within the active moiety; wherein the energy transferred from the photosensitizer is sufficient to cause a chemical reaction in the active moiety, wherein the composition does not comprise an annihilator.

23. A method comprising directly transferring energy from a photosensitizer to an active moiety by triplet-triplet energy transfer to cause a chemical reaction in the active moiety, wherein the energy is not transferred by an annihilating agent.

24. A method comprising administering to a subject a composition comprising a photosensitizer to transfer triplet-triplet energy from the photosensitizer to a cleavable moiety to cause cleavage of the cleavable moiety; and applying light to the subject to cause cleavage of the cleavable moiety, wherein the triplet-triplet energy is not transferred by the annihilating agent.

25. The method of claim 24, wherein the light is coherent.

26. The method of claim 24, wherein the light is incoherent.

1. Field of the invention

The present invention relates generally to various light-triggered drug release and photoreactions, including reactions that are typically based on triplet-triplet energy transfer using photoexcitation.

2. Background of the invention

Drug delivery plays an important role in cancer treatment. Site-specific and controlled drug release is highly desirable because it allows for reduced drug dosage, to reduce side effects and to improve therapeutic efficacy. To address this problem, a variety of stimulus-responsive drug delivery systems have been developed^[1]. Stimuli employed in these drug delivery systems include light, pH, electric/magnetic fields, ultrasound, heat, specific biomolecules, and the like. The light irradiation can be easily operated with controllable power and exposure time compared to other stimuli. Furthermore, the development of laser beam technology also provides an effective solution for the precise release of drugs in tumors, which makes light-responsive drug delivery a promising strategy in cancer medicine today^[2]。

Photoresponsive systems usually comprise photoisomerizable groups (azobenzenes, spiropyrans and dithienylethylenes) or photocleavable groups (o-nitrobenzyl and coumarin-4-ylmethyl) whose chemical structure changes upon optical excitation^[3]. However, these photoresponsive groups typically require Ultraviolet (UV) light excitation, which limits their tissue penetration depth and can be toxic to cells because most biomolecules have UV absorption. One solution to increase the excitation wavelength is to change the conjugated structure of the photoresponsive group. However, the photoresponsive properties (e.g. the quantum yield of the photoreaction) are uncertain and the required organic synthesis will also be time consuming and laborious. An alternative approach is to use an upconversion luminescence (UCL) system that emits UV light upon excitation with visible or near infrared light, including rare earth doped upconversion nanoparticles (UCNPs) and triplet-triplet annihilation upconversion (TTA-UC) systems^[4]. The UV light emitted by the UCL system is further used to activate the photo-responsive groups. For example, Shi and coworkers developed an NIR light-triggered drug delivery system by coating UCNP with azobenzene-modified mesoporous silica^[5]. Li and coworkers synthesized coumarin-modified prodrugs, which were further loaded into egg yolk-shell UCNP for drug release triggered by 980nm light excitation^[6]. However, the upconversion efficiency of UCNP is very low (at 150W/cm)²Absolute quantum efficiency of only about 0.1% under the irradiation conditions of (1)^[4a]. Therefore, in conducting in vitro or in vivo studies, high excitation power is required, which rapidly increases the temperature around the irradiated area and is harmful to healthy tissue.

Compared with UCNP, another up-conversion system TTA-UC has higher up-conversion efficiency (up to 20%)^[4a]. Previously, we reported a light-triggered targeting system using TTA-UCL as an energy donor, which activates (7-diethylaminocoumarin-4-yl) methyl (DEACM) -modified c [ R ] with green light (530nm) irradiation]Targeting function of GDfK^[7]. Han and colleagues further developed a TTA-UC system with a novel pair of photosensitizer and annihilator that achieves red light triggered drug release^[8]. Both systems can be triggered in vivo with low power density LED light, indicating a more promising application in medicine. However, the quantum yield of TTA-UCL is theoretically below 0.5, since the emission of one up-converted photon (UV light) requires the absorption of two photons of longer wavelength (visible or NIR light)^[4a]. In addition, the method can be used for producing a composite materialTTA-UCL involves a multi-step intramolecular and intermolecular energy transfer process. Most of the absorbed energy will be dissipated in an unexpected way, resulting in low UCL quantum efficiency and low light-triggered drug release efficiency. Therefore, new strategies are highly desirable for developing efficient photo-responsive drug delivery systems employing long wavelength excitation.

Light responsive drug delivery systems have shown great potential in the spatiotemporal control of drug release. However, most of these systems require Ultraviolet (UV) light excitation, which limits the penetration depth of the tissue and may be toxic to the cells. It is therefore important to develop a photo-activation strategy that uses light of longer wavelength than the absorption window of the photo-responsive group with high efficiency.

3. Overview

The present invention relates generally to various light-triggered drug release and photoreaction based on triplet-triplet energy transfer with long wavelength light excitation. In one aspect, the present invention generally relates to a composition. In one set of embodiments, the composition comprises a photosensitizer, a cleavable moiety capable of receiving energy from the photosensitizer in a higher energy state to cause cleavage of the cleavable moiety, and a releasable moiety releasable from the composition upon cleavage of the cleavable moiety.

In yet another set of embodiments, the composition comprises a carrier material comprising a photosensitizer, an active moiety, and a releasable moiety. In some embodiments, absorption of an incident photon by the photosensitizer causes energy to be transferred to the photosensitizer, and then to the active moiety, thereby causing a chemical reaction within the active moiety. In one set of embodiments, the composition comprises a photosensitizer capable of absorbing photons to produce a higher energy state, a triplet-triplet energy transfer from the photosensitizer to a cleavable moiety capable of causing cleavage of the cleavable moiety, and a releasable moiety releasable from the composition upon cleavage of the cleavable moiety. According to another set of embodiments, the composition comprises a photosensitizer capable of directly sensitizing the cleavable moiety through the triplet-triplet transfer process (TTET). In one embodiment, the composition does not contain an annihilating agent.

In another aspect, the present invention is generally directed to a method. According to one set of embodiments, the method includes absorbing a photon in a photosensitizer, transferring energy directly from the photosensitizer to an active moiety by triplet-triplet energy transfer, generating an excited state of a cleavable moiety by triplet-triplet energy transfer, and using the transferred energy to cause a chemical reaction in the active moiety.

In another set of embodiments, the method comprises administering to the subject a composition comprising a photosensitizer, a cleavable moiety capable of receiving a triplet-triplet energy transfer from the photosensitizer to cause cleavage of the cleavable moiety, and applying light to at least a portion of the subject to cause cleavage of the cleavable moiety.

In yet another set of embodiments, the method comprises administering to the subject a composition comprising a photosensitizer, a cleavable moiety, and a carrier material, and applying light to the subject. In some cases, absorption of light by the photosensitizer causes energy to be transferred to the cleavable moiety, thereby causing cleavage of the cleavable moiety.

In yet another set of embodiments, the method comprises administering to a tumor of the subject a composition comprising a photosensitizer, a cleavable moiety, and a carrier material, and applying light to at least a portion of the tumor, wherein absorption of light by the photosensitizer results in energy transfer to the cleavable moiety, thereby resulting in cleavage of the cleavable moiety.

In another aspect, the invention encompasses methods of making one or more embodiments described herein, e.g., compositions comprising a photosensitizer and a cleavable moiety. In yet another aspect, the invention encompasses methods of using one or more embodiments described herein, e.g., a composition comprising a photosensitizer and a cleavable moiety.