Patent Description:
The invention generally relates to nano-materials and compositions. More particularly, the invention relates to an upconversion composition, a compound of structural formula (I), a biocompatible nanoparticle delivery system, a pharmaceutical composition, a biocompatible nanoparticle for use in a method for treating tumor or cancer, and a compound or a nanoparticle delivery system for use in the treatment of cancer or tumor, as defined in the claims. Such materials and nanoparticles may be used for stimulus-responsive, in situ delivery of biologically active agents.

Recently, stimulus-responsive prodrug release and delivery systems have attracted growing interest in the fields of chemistry and biology. Studies have shown improved therapeutic efficacy from drug release in malignant sites with minimal off-targeting side effects. (<NPL>; <NPL>; <NPL>. ) Compared to other drug release strategies, light-induced prodrug activation is unique, with noninvasive operations and high spatiotemporal controllability. (<NPL>; <NPL>; <NPL>.

In light-induced prodrug activation, drug molecules are typically modified and protected with light sensitive chromophores, such as coumarin, <NUM>-nitrobenzyl and <NUM>-nitroindoline. However, these chromophores typically require short wavelength, e.g., deep blue light (∼<NUM>) or phototoxic ultraviolet (UV) light (∼<NUM>), as the excitation light sources, which unfortunately suffer from rather poor tissue penetration depth in in vivo applications. (<NPL>; <NPL>; <NPL>; <NPL>.

To address such shortcomings, long wavelength light has recently been utilized in the therapeutic window (<NUM>-<NUM>) due to its minimal absorption by tissue and deep tissue penetration. (<NPL>;<NPL>;<NPL>; <NPL>; <NPL>. ) For example, lanthanide ion-doped inorganic upconversion nanoparticles (UCNPs) have the ability to convert tissue penetrable long wavelength light into high-energy short wavelength photons in order to trigger small molecule drug release. (<NPL>; <NPL>.

Challenges remain, however, in regard to inorganic UCNPs. For instance, due to the intrinsic low absorption and emission cross-sections of the contained lanthanide ions, such UCNPs have low quantum yields that typically require high power density laser excitation. In addition, the long-term in vivo toxicity and systematic clearance of inorganic lanthanide ions inside UCNPs are unknown. (<NPL>; <NPL>; <NPL>.

<NPL>, discloses perylene-derived triplet acceptors with optimized excited state energy levels for triplet-triplet annihilation assisted upconversion.

<NPL> discloses an organic triplet sensitizer library derived from a single chromophore (BODIPY) with long-lived triplet excited state for triplet-triplet annihilation based upconversion.

<NPL> discloses Bodipy-anthracene dyads as triplet photosensitizers.

<NPL> discloses light-harvesting fullerene dyads as organic triplet photosensitizers for triplet-triplet annihilation upconversions.

There is an ongoing need for novel materials and improved upconversion that are suitable for stimulus-responsive, in situ delivery of biologically active agents thereof.

The invention provides an upconversion composition, a compound of structural formula (I), a biocompatible nanoparticle delivery system, a pharmaceutical composition, a biocompatible nanoparticle for use in a method for treating tumor or cancer, and a compound or a nanoparticle delivery system for use in the treatment of cancer or tumor, as defined in the claims. Such materials and nanoparticles may be used for stimulus-responsive, in situ delivery of biologically active agents for a wide range of clinical applications.

A key disclosure is the unconventional strategy to expand anti-Stokes shift from the red region or far-red region to the deep-blue region in a metal-free, triplet-triplet annihilation upconversion (TTA-UC) strategy.

Another key disclosure is the in vivo photo-triggered release of a therapeutic agent, e.g., an anticancer prodrug, upon delivery to a target disease site.

The TTA system disclosed herein exhibits robust brightness and, to our knowledge, the longest anti-Stokes shift of any reported TTA system. Also disclosed herein are TTA core-shell-structured prodrug delivery capsules that can operate with low-power-density red or far-red light-emitting diode (LED) light.

For example, capsules are disclosed that contain mesoporous silica nanoparticles preloaded with TTA molecules as the core and amphiphilic polymers encapsulating anticancer prodrug molecules as the shell. When stimulated by red or far-red light, the intense TTA upconversion blue emission in the system activates the anticancer prodrug molecules and shows effective tumor growth inhibition in vivo.

As promising alternatives to inorganic UC systems, the disclosed invention paves the way for the utilization of organic TTA upconversion in photocontrollable in vivo drug release and other biophotonic applications.

In one aspect, the invention generally relates to an upconversion composition, comprising an organic triplet photosensitizer molecule and an organic emitter molecule, wherein the composition is characterized by an upconversion upon excitation in the red region of <NUM> to <NUM> or far red region of <NUM> to <NUM> with an emission in the deep blue region of <NUM> to <NUM>, wherein each of the triplet photosensitizer and emitter molecules comprises no metallic elements, wherein the triplet photosensitizer molecule has the structural formula (I):
<CHM>
wherein.

wherein the organic emitter molecule is <NUM>-phenylacetylene anthracene.

In another aspect, the invention generally relates to a compound having the structural formula (I):
<CHM>
wherein.

each R<NUM> is independently selected from the group consisting of: H and alkyl.

In yet another aspect, the invention generally relates to a biocompatible nanoparticle delivery system, comprising: a triplet photosensitizer molecule and an emitter molecule, wherein each of the triplet photosensitizer and emitter molecules is an organic molecule and comprises no metallic elements; the triplet photosensitizer is excited by a light in in the red region of <NUM> to <NUM> or far red region of <NUM> to <NUM> causing an emission by the emitter molecule in the deep-blue region of <NUM> to <NUM>; and a photolabile molecule comprising a coumarin moiety and a biologically active agent, wherein the biologically active agent is releasable upon absorption of the emission by the emitter molecule, wherein the triplet photosensitizer molecule has the structural formula (I):
<CHM>
wherein.

wherein the emitter molecule is <NUM>-phenylacetylene anthracene.

In yet another aspect, the invention generally relates to a pharmaceutical composition comprising a compound or a nanoparticle delivery system as defined in the claims.

In yet another aspect, the invention generally relates to a biocompatible nanoparticle for use in a method for treating tumor or cancer, wherein the biocompatible nanoparticle comprises: a triplet photosensitizer molecule and an emitter molecule, wherein each of the triplet photosensitizer and emitter molecules is an organic molecule and comprises no metallic elements; the triplet photosensitizer is excited by a light in the red region of <NUM> to <NUM> or far red region of <NUM> to <NUM> causing an emission by the emitter molecule in the deep blue region of <NUM> to <NUM>; and a photolabile molecule comprising a coumarin moiety and an antitumor or anticancer agent, wherein the antitumor or anticancer agent is releasable upon absorption of the emission by the emitter molecule, wherein the triplet photosensitizer molecule has the structural formula (I):
<CHM>
wherein.

wherein the method for treating tumor or cancer comprises:.

In yet another aspect, the invention relates to a compound or a nanoparticle delivery system for use in the treatment of cancer or tumor as defined in the claims.

The invention relates to an upconversion composition, a compound having the structural formula (I), a biocompatible nanoparticle delivery system, a pharmaceutical composition, a biocompatible nanoparticle for use in a method for treating tumor or cancer, and a compound or a nanoparticle delivery system for use in the treatment of cancer or tumor, as defined in the claims.

The invention is based in part on the unexpected discovery of a novel class of nano-materials characterized by triplet-triplet annihilation upconversion (TTA-UC), and compositions thereof, as defined in the claims. Such materials and nanoparticles thereof may be used for stimulus-responsive, in situ delivery of biologically active agents for a wide range of clinical applications.

The disclosed strategy of metal-free triplet-triplet annihilation unconventional expands anti-Stokes shifting from the far red to deep blue region, which is utilized in in vivo photorelease of a therapeutic agent (e.g., an anticancer prodrug). The triplet-triplet annihilation upconversion strategy demonstrated herein affords robust brightness and the record longest anti-Stokes shift from far red to deep blue. In addition, TTA nanocapsules (e.g., core-shell structured) for photo-triggered prodrug release provided herein operates with a low-power density, far red LED light (<NUM>) and shows effective and efficient prodrug activation control and potent tumor-growth inhibition in vivo.

Due to its unique spatio-temporal control ability, photo-uncaging has recently been studied for disease therapy. Usually, photo-uncaging reaction depends on UV and deep blue light irradiation. However, the short wavelength light is limited in biological application due to high phototoxicity for cells and tissue and shallow tissue penetration. Photo-uncage reagents generally require two-photon near infrared excitations from pulse lasers to simulate UV and deep blue radiation, making such a process very expensive.

While rare earth-doped inorganic UCNPs have realized photo-uncaging with near infrared light irradiation (<NUM> or <NUM>), major challenges remain in regard to inorganic UCNPs. For instance, due to the intrinsic low absorption and emission cross-sections of the contained lanthanide ions, such UCNPs have very low quantum yields and generally require high power density laser excitation. In addition, the long-term in vivo toxicity and systematic clearance of inorganic lanthanide ions inside UCNPs are also unclear.

Green to blue TTA-UC nanomicelles were recently reported to trigger the uncaging of blue light sensitive coumarin group modified peptides, thus enabling better subsequent cell targeting. ) However, in vivo drug photorelease and concomitant cancer treatment have been formidable challenges because the green excitation source lacks deep issue penetration depth and yields low quantum efficiency. Moreover, such TTA-UC remains insufficient to activate large amount of prodrug molecules for cancer treatment. ) To address this problem, certain deep tissue penetrable longer wavelength light excitable TTA system were proposed. For example, a TTA system containing meso-tetraphenyl-tetrabenzoporphine palladium PdTPBP (sensitizer) and perylene (emitter) can upconvert <NUM> laser light to <NUM> photons and was used for the photodissociation of ruthenium polypyridyl complexes from PEGylated liposomes in water. However, the existing system has limitations in biological in vivo applications due to its suboptimal efficiency and relatively high excitation power density (<NUM> W/cm<NUM>), which is beyond the biosafety threshold. ) In addition, the anti-Stokes shifted emission wavelength of <NUM> is not compatible with the typical deep blue/UV operation wavelengths for biologically used caging groups. (<NPL>; <NPL>; <NPL>.

Herein disclosed is a metal-free, biocompatible upconversion strategy, in particular exploring organic chromophore-based TTA-UC. This strategy is demonstrated to expand anti-Stokes shifting from in the red region (from <NUM> to <NUM>) or far red region (from <NUM> to <NUM>) to the deep blue region (from <NUM> to <NUM>) in metal-free TTA-UC and is suitable for in vivo titrating anticancer prodrug photorelease.

As illustrated in Scheme 1a, low energy photons can be absorbed by a sensitizer chromophore and can then be transferred to an acceptor chromophore through a unique triplet-triplet energy transfer process. Two excited acceptor molecules subsequently underwent TTA annihilation process, generating one high-energy short wavelength photon. <CHM>
(a) A Jablonski diagram of the photophysical processes of the triplet photosensitizers and the TTA upconversion exemplified with BDP-F as the triplet photosesitizer and PEA as the emitter; (b) Molecular structure of BDP-F and PEA.

Benefiting from the robust brightness and long anti-Stokes shift, a novel TTA core-shell-structured prodrug delivery system is provided herein that can be operated with a low power density far red-LED light (<NUM>). For example, the delivery system employs mesoporous silica nanoparticles preloaded with TTA molecules as the core and amphiphilic polymers encapsulating anti-cancer prodrug molecules as the shell. When stimulated by far red light (<NUM>), the intense TTA upconversion blue emission activated the anticancer prodrug molecules and showed effective tumor growth inhibition in vivo. This invention paves the way for the use of organic TTA upconversion systems in various biophotonic applications with in vivo photo-controllable drug release.

Comparing to inorganic UCNPs, the TTA-UC system disclosed herein offers significant advantages due to its intense absorption coefficient of sensitizers, high quantum yield and brightness, as well as the concomitant low power density excitation resource. (<NPL>; <NPL>; <NPL>; <NPL>; <NPL>.

The TTA-UC system possesses dramatically improved anti-Stokes shift, coupled with highly desirable robust brightness and biocompatibility, allowing the present system to be applicable in various applications as photo-controllable drug delivery systems.

In addition, novel photosensitizers and emitters are employed, which together achieve large antistokes shift from far red or near infrared (NIR) excitation to deep-blue emission with low power intensity excitation. <CHM>
Molecular structure of photosensitizer -BDP-F substituted functional groups (R's as defined herein).

Thus, in one aspect, the invention generally relates to an upconversion composition, comprising an organic triplet photosensitizer molecule and an organic emitter molecule, wherein the composition is characterized by an upconversion upon excitation in the red region of <NUM> to <NUM> or far red region of <NUM> to <NUM> with an emission in the deep blue region of <NUM> to <NUM>, wherein each of the triplet photosensitizer and emitter molecules comprises no metallic elements, wherein the triplet photosensitizer molecule has the structural formula (I):
<CHM>
wherein.

In certain embodiments, excitation is in the region of <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, or <NUM> to <NUM>.

In certain embodiments, emission in the region of <NUM> to <NUM>, <NUM> to <NUM>, or <NUM> to <NUM>.

The triplet photosensitizer molecule has the structural formula (I):
<CHM>
wherein.

In certain embodiments of the composition, R<NUM> is selected from the group consisting of: phenylethynyl, naphthalene ethynyl, carbazole ethynyl and fluorenyl ethynyl.

In certain embodiments of the composition, R<NUM> is selected from the group consisting of:
<CHM>
<CHM>
wherein each R<NUM> is independently a C<NUM>-C<NUM> (e.g., C<NUM>H<NUM>) alkyl group.

Any suitable molar ratios of triplet photosensitizer : emitter may be employed, e.g., from <NUM> : <NUM> to <NUM> : <NUM>, from <NUM> : <NUM> to <NUM> : <NUM>, from <NUM> : <NUM> to <NUM> : <NUM>.

In certain embodiments, the composition further includes an unsaturated olefin (e.g., those listed in Scheme <NUM>).

In certain embodiments of the compound, R<NUM> is selected from the group consisting of: phenylethynyl, naphthalene ethynyl, carbazole ethynyl and fluorenyl ethynyl.

In certain embodiments of the compound, R<NUM> is selected from the group consisting of:
<CHM>
<CHM>
wherein each R<NUM> is independently a C<NUM>-C<NUM> (e.g., C<NUM>H<NUM>) alkyl group.

In certain embodiments of the compound, each of R<NUM> and R<NUM> is H, R<NUM> is I, R<NUM> is a substituted or unsubstituted fluorenyl ethynyl, and each R<NUM> is methyl.

In yet another aspect, the invention generally relates to a biocompatible nanoparticle delivery system. The system includes: a triplet photosensitizer molecule and an emitter molecule, wherein each of the triplet photosensitizer and emitter molecules is an organic molecule and comprises no metallic elements; the triplet photosensitizer is excited by a light in the red region of <NUM> to <NUM> or far red region of <NUM> to <NUM> causing an emission by the emitter molecule in the deep blue region of <NUM> to <NUM>; and a photolabile molecule comprising a coumarin moiety and a biologically active agent, wherein the biologically active agent is releasable upon absorption of the emission by the emitter molecule, wherein the triplet photosensitizer molecule has the structural formula (I):
<CHM>
wherein.

In certain embodiments of the system, the nanoparticle is characterized by a core-shell structure, wherein the triplet photosensitizer molecule and an emitter molecule are deposed in the core whereas the photolabile molecule is deposed in the shell.

In certain embodiments of the system, R<NUM> is selected from the group consisting of: phenylethynyl, naphthalene ethynyl, carbazole ethynyl and fluorenyl ethynyl.

In certain embodiments of the system, R<NUM> is selected from the group consisting of:
<CHM>
<CHM>
wherein each R<NUM> is independently a C<NUM>-C<NUM> (e.g., C<NUM>H<NUM>) alkyl group.

In certain embodiments of the system, the biologically active agent is an anti-cancer agent.

The photolabile molecule comprises a coumarin moiety.

In certain embodiments of the system, the anti-cancer agent is chlorambucil.

In certain embodiments, the system further includes an unsaturated olefin (e.g., those listed in Scheme <NUM>).

In yet another aspect, the invention generally relates to a pharmaceutical composition comprising a nanoparticle delivery system or the compound disclosed herein.

In certain embodiments, emission in the region of <NUM> to <NUM>, <NUM> to <NUM>, <NUM> <NUM>.

The photolabile molecule comprises a coumarin moiety and an antitumor or anticancer agent.

In certain embodiments, the anti-cancer agent is chlorambucil.

In certain embodiments, R<NUM> is selected from the group consisting of: phenylethynyl, naphthalene ethynyl, carbazole ethynyl and fluorenyl ethynyl.

In certain embodiments, each of R<NUM> and R<NUM> is H, R<NUM> is I, R<NUM> is a substituted or unsubstituted fluorenyl ethynyl, and each R<NUM> is methyl.

In certain embodiments, R<NUM> is selected from the group consisting of:
<CHM>
<CHM>
wherein each R<NUM> is independently a C<NUM>-C<NUM> (e.g., C<NUM>H<NUM>) alkyl group.

In certain embodiments, the biocompatible nanoparticle further includes an unsaturated olefin (e.g., those listed in Scheme <NUM>).

As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., C<NUM>-<NUM> alkyl). Whenever it appears herein, a numerical range such as "<NUM> to <NUM>" refers to each integer in the given range; e.g., "<NUM> to <NUM> carbon atoms" means that the alkyl group can consist of <NUM> carbon atom, <NUM> carbon atoms, <NUM> carbon atoms, etc., up to and including <NUM> carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, "alkyl" can be a C<NUM>-<NUM> alkyl group. In some embodiments, alkyl groups have <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, or <NUM>-<NUM> carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, <NUM>-methylbutyl, <NUM>-methylbutyl, <NUM>-methylpentyl, <NUM>-methylpentyl, <NUM>-methylpentyl, <NUM>-methylhexyl, <NUM>-methylhexyl, <NUM>-methylhexyl, <NUM>-methylhexyl, <NUM>,<NUM>-dimethylbutyl, and the like. The alkyl is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted by one or more of substituents (e.g., acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(Ra)<NUM> , -ORa, -SRa, -OC(O)-Ra, -N(Ra)<NUM>, - C(O)Ra, -C(O)ORa, -OC(O)N(Ra)<NUM>, -C(O)N(Ra)<NUM>, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, - N(Ra)C(O)N(Ra)<NUM>, -N(Ra)C(NRa)N(Ra)<NUM>, -N(Ra)S(O)tN(Ra)<NUM> (where t is <NUM> or <NUM>), -P(=O)(Ra)(Ra), or -O-P(=O)(ORa)<NUM> where each Ra is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein). In a non-limiting embodiment, a substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, <NUM>-fluoroethyl, <NUM>-fluoropropyl, hydroxymethyl, <NUM>-hydroxyethyl, <NUM>-hydroxypropyl, benzyl, and phenethyl.

The herein disclosed organic TTA upconversion system not only offers a new nanoplatform for spatio-temporal controlled cancer therapy, but also has great potential for numerous photonic and biophotonic applications.

A TTA-UC system was synthesized having a far-red absorption photosensitizer-BDP-F and deep blue emitter-PEA. A metal-free iodized BODIPY dimer (BDP-F) molecule was used as a highly far red-sensitive photosensitizer and <NUM>-phenylacetylene anthracene (PEA) as a deep blue emitter (Scheme 1b). Compared to conventional BODIPY photosensitizers, such as <NUM>, <NUM>-diiodio-BODIPY (ε = <NUM><NUM>-<NUM>cm-<NUM> at <NUM>, Scheme <NUM>), due to the large π-core, BDP-F presented broader and more intense absorption in the far-red region from <NUM> to <NUM> (peaking at <NUM>, ε= <NUM>×<NUM><NUM>M-<NUM> cm-<NUM>; <FIG>).

Meanwhile, BDP-F has an outstanding triplet state lifetime (τT = <NUM>; <FIG>) that is essential for the TTA photosensitizers. To increase the anti-Stokes shifted deep blue emission, <NUM>-phenylacetylene anthracene (PEA) was synthesized as a new emitter (Scheme <NUM>). Such PEA has presented excellent fluorescence quantum yield in the deep blue region from <NUM> to <NUM>, peaking at <NUM> (Φf= <NUM>%; <FIG>), making it particularly suitable to act as the emitter.

Further optimized was the concentration ratio of BDP-F and PEA in the TTA-UC system. It was found that their best combination was at <NUM> for BDP-F and <NUM> for PEA in degassed toluene solution (<FIG>). Under such an optimal ratio, intense deep blue emission in the range of <NUM>-<NUM> can be observed by the naked eye under the irradiation of <NUM> light (<FIG>). This TTA-UC system showed high a relative upconversion quantum yield (ΦUC = <NUM>%) by using methyl blue as a reference. The TTA-UC also presented excellent upconversion brightness (η= ε × ΦUC, <NUM> at <NUM> mW/cm<NUM> of <NUM>).

To the best of our knowledge, the TTA-UC system presents the longest anti-Stokes shift (Δλ = <NUM> eV) among all the reported TTA upconversion systems (Table <NUM>). Further, the TTA upconversion intensity threshold (Ith) was studied (<FIG>). The quadratic dependence of the upconversion emission was indeed observed for low-energy incident power density excitation and the linear region observed at higher incident power densities in deaerated toluene. The transition threshold (Ith) between the quadratic and the linear regime occurs near <NUM> mW cm-<NUM>, which is comparable to reported TTA-UC systems (<NPL>). Power dependence experiment provides solid evidence for TTA-UC in BDP-F and PEA system in deaerated toluene.

Due to such excellent photophysical properties, we then sought to construct a TTA-UC drug delivery system based on this new TTA system. In particular, we designed a TTA upconversion core/shell structured nanocapsule (TTA-CS). In the TTA-CS, TTA-MSNs as core structrue are the TTA-UC nanoparticles with the TTA-UC dye pair, but without any photosensitive drug, while TTA-CS is the upconverting nanoparticles loaded with the deep blue light sensitive and hydrophobic prodrug (coumarin-chlorambucil (Cou-C), molecular structure <FIG>) (<NPL>) (Scheme <NUM>). After uncaging, the prodrug (Cou-C) is able to convert to hydrophilic chlorambucil which can release from TTA-CS and then kill the tumor cells.

An important finding was that a series of unsaturated olefins can efficiently prevent oxygen quenching to TTA-UC. For example, the following unsaturated olefins can efficiently prevent oxygen quenching the TTA-UC in the air.

It was found that methyl oleate oil can efficiently prevent oxygen quenching to TTA-UC, as can be seen in <FIG>, Compared to in the argon condition, only <NUM> % upconversion intensity reduced in the air. In addition, TTA-UC system of BDP-F and PEA in the methyl oleate was quite stable, even after <NUM> days, the upconversion emission intensity was reduced by only <NUM> % in the present of air (<FIG>). And then, TTA-UC (<NUM> of BDP-F and <NUM> of PEA) in methyl oleate oil was infused into mesoporous channels of silica nanoparticles to form TTA-MSNs.

The TTA-MSNs were characterized by transmission electron microscopy (TEM). As shown in <FIG>, the TEM image indicates that the TTA-MSNs consist of uniform spherical nanoparticles with a diameter of <NUM> ± <NUM>. The hydrodynamic diameter is <NUM> ± <NUM> as measured by the dynamic light scatter technique (DLS) in DI water. As shown in <FIG>, upon <NUM> light excitation, TTA-MSNs generated a deep bright blue upconversion emission that peaks at <NUM>. Using methyl blue as the reference, the upconversion quantum yield (ΦUC) of TTA-MSNs in water was measured to be <NUM> % (<NUM> mW cm-<NUM>) in the air. In addition, the photostability of TTA-MSNs was also investigated in the air. No significant changes in the TTA-UC were observed when TTA-MSNs were continuously irradiated by the <NUM> laser (<NUM> mW cm-<NUM>) for <NUM>. This indicates the excellent photostability of TTA-MSNs.

Secondly, as shown in Scheme <NUM>, TTA-CS was prepared by deep blue light sensitive hydrophobic prodrug (<NPL>) and TTA-MSNs co-encapsulated with amphiphilic polymer F-<NUM> (TTA-CS). In TTA-CS, Chlorambucil was chosen because it has been reported to be a potent and cost-effective small molecule tumor inhibitor (<NPL>; <NPL>.

Moreover, the coumarin-based group possesses high photocleavage efficiency and deep blue absorption wavelength, the latter of which overlaps with the emission spectrum of PEA (<FIG>). As can be seen in <FIG>, the deep blue upconversion emission of the resulting TTA-CS is less than TTA-MSNs, suggesting that the prodrug (Cou-C) that absorbs the <NUM> light was successfully encapsulated within the system. The core/shell nanocapsule was further characterized by use of the DLS technique. The hydrodynamic diameter of the TTA-CS (<NUM> ± <NUM>) is larger than the diameter of TTA-MSNs (<FIG>), indicating that the presence of the amphiphilic polymer F-<NUM> encapsulated prodrug is the external shell in the system. The prodrug entrapment efficiency was calculated by a previously reported method to be <NUM>%. We found that the release of prodrug out of TTA-CSs in absence of <NUM> light is in fact rather insignificant (∼<NUM>% after <NUM>).

Next tested was the feasibility of prodrug activation using our TTA-CS system (<FIG>). The activation of the prodrug process was quantified by the fluorescence measurement because the fluorescence of coumarin moiety at <NUM> decreases when it is removed from chlorambucil molecules (<FIG>). As shown in <FIG>, when we irradiated TTA-CS with <NUM> LED (<NUM> mW/cm<NUM>), the prodrug was uncaged, resulting in > <NUM> % activation of the prodrug within <NUM>. , and a maximum photorelease of ~<NUM> % of the prodrug after <NUM>.

These results confirmed that the prodrug can be activated by the TTA-upconversion process by far red light. As a control, a similar nanocapsule consisting of the photosensitizers without the PEA emitter (termed BDP-F-CS) was designed as a non-emissive control. Excluding the possibility of the direct uncaging of chlorambucil by <NUM> light (<FIG>), upon <NUM> irradiation of BDP-F-CS for <NUM>. , no observable uncaged chlorambucil was detected. Moreover, the photorelease of chlorambucil was clearly dependent on the on-off pattern of the LED excitation source (<FIG>). This indicates that the release dose and duration can be precisely titrated by far red light under a low power density of <NUM> mW cm-<NUM>.

To demonstrate in vitro effectiveness of our system, cell viability experiments were conducted. After the cancer cells (Hela and 4T1 cells) incubated with TTA-CS for <NUM>, the low-power far-red LED was used. As shown in <FIG>, TTA-MSNs have insignificant toxicity with and without light. In addition, TTA-CS presented negligible cell toxicity in the absence of LED light (the concentration range from <NUM> to <NUM>µg / mL). However, upon far red LED irradiation, TTA-CS presented significant cell toxicity for both Hela and 4T<NUM> cells, suggesting Cou-C is successfully photocleaved by TTA-UC and the hydrophilic anticancer chlorambucil is indeed released from TTA-CS into the cells, causing cancer cell death (<FIG>). The IC<NUM> under light irradiation (half-maximal concentration of TTA-CS and Cou-C to cause cell death) was calculated to be <NUM> ±<NUM>µg/mL and <NUM>µg/mL with Hela cells, <NUM> ± <NUM>µg/mL and <NUM>µg/mL with 4T<NUM> cells respectively.

Far red light mediated prodrug photorelease was also evaluated by the calcein-AM/PI co-staining method. ) In the absence of far-red LED irradiation, we only observed bright green emission in the cancer cells, suggesting that TTA-CS itself did not kill cancer cells. However, In the presence of far-red LED irradiation, red emission suggesting the cell deaths was observed in the cells. As a control, we did not observe significant cell death with prodrug-free core nanoparticles (TTA-MSNs) in the presence of LED irradiation (<FIG>). These results further demonstrated that far-red light triggered TTA upconversion can activate prodrug photorelease and lead to cancer cells growth inhibition.

Since TTA-CS showed excellent cancer cell inhibition in vitro, we then continue testing TTA-UC-induced prodrug release in vivo. First, we prepared 4T<NUM> tumor-bearing mice and divided them into four experiment groups (Group <NUM>: only PBS injection + irradiation; Group <NUM>: TTA-CS injection but no irradiation; Group <NUM>: TTA-MSNs and irradiation; Group <NUM>: TTA-CS injection and irradiation). After <NUM>. of intra-tumor injection, tumor sites were then irradiated with a far-red LED (<NUM> mW/cm<NUM>). The treatment outcome of TTA-CS to tumor was assessed by monitoring relative tumor volumes in mice, and tumor tissue ablation was also evaluated by H&E staining on tissue sections.

As shown in <FIG>, no tumor growth inhibition or tumor tissue necrosis was observed in Group <NUM>. Group <NUM> showed no tumor growth inhibition or tumor tissue necrosis, which indicates that TTA-CS itself cannot inhibit tumor growth. Group <NUM> also demonstrated insignificant cancer treatment efficiency, suggesting low power red LED we used has little photothermal or other effects for cancer cell killing. In marked contrast, the tumor growth in Group <NUM> was remarkably suppressed, and the tumor tissue showed obvious necrosis. These results indicate that the deep blue upconversion induced chlorambucil release from the prodrug (Cou-C) does lead to tumor tissue ablation. To the best of our knowledge, this is the first time that TTA-UC-induced photocleavage-based prodrug photorelease has been realized in vivo upon low power far-red LED irradiation.

In order to determine the potential toxicity and side effects of TTA-CS, the mice's body weight loss was measured. As shown in <FIG>, mice treated with TTA-CS did not show apparent weight loss. After <NUM> days by an intravenous injection of TTA-CS, the treated mice and untreated age-matched healthy mice were sacrificed, and the major organs including heart, liver, spleen, lung, and kidney were collected for H&E staining to evaluate the toxic effect. No noticeable sign of organ damage was observed on the H&E-stained organ slices, which suggests that TTA-CS is safe for in vivo cancer treatment applications (<FIG>). Further, the serum analysis experiment was performed, as shown in Table <NUM>, and no abnormal results were observed from this serum analysis, which suggests that no observable inflammation was induced.

All reagents and solvents were used as received without further purification unless otherwise indicated. Methyl oleate, <NUM>,<NUM>-dimethylpyrrole, trimethylsilylacetylene, copper iodide, dichlorobistriphenylphosphine palladium (Pd(PPh<NUM>)Cl<NUM>), <NUM>-bromo-anthracene, phenylacetylene, dry tetrahydrofuran (THF) were purchased from Sigma-Aldrich. Analytical grade toluene, methanol, CHCl<NUM>, CH<NUM>Cl<NUM>, THF, and dimethylformamide (DMF) were purchased from Fisher Scientific. Deionized water was used in the experiments.

The compounds were characterized by <NUM>H-NMR, <NUM>C-NMR, ESI-HRMS and FT-IR. The purified of BDP-F and PEA was characterized by HLPC (C<NUM> reverse phase column, eluent: CH<NUM>CN containing <NUM> % TFA). <NUM>H-NMR and <NUM>C-NMR spectra were obtained on a Bruker <NUM> NMR spectrometer, tetramethylsilane (TMS) as internal standard (<NUM> ppm) substances, and CDCl<NUM> as solvent. Agilent Cary <NUM>, UV-Vis spectrometer was used to measure the UV-vis absorption spectra, and a HITACHI F-<NUM> fluorescence spectrometer with <NUM> W xenon lamps was utilized to obtain the steady-state emission spectra and Fluorescence lifetimes were measured on an OB920 luminescence lifetime spectrometer.

The nanosecond time resolved transient absorption spectra were detected by an LP920 laser flash photolysis spectrometer. The transient signals were recorded on a digital oscilloscope. The lifetime values by monitoring the decay trace of the transients were obtained with LP900 software.

All samples in flash photolysis experiments were deaerated with Ar for ca. before measurement, and the gas flow was maintained during the measurements. The morphology of the TTA-MSNs nanoparticles was characterized at a JEOL JEM-200CX transmission electron microscope (TEM) operated at <NUM> kV.

The sample for TEM measurement was prepared by dropping the solution onto a carbon coated copper grid. The particle size and size distribution of TTA-CS and TTA-MSNs were measured by dynamic light scattering (DLS) using a Mastersizer <NUM> particle size analyzer, laser wavelength is <NUM>. For the TTA upconversion spectra measurement, the diode pumped solid-state laser (<NUM>, continues wave, CW, Hi-Teach company, China) was used to excitation light source, and a modified spectrofluorometer was used to record the upconversion spectra. For the prodrug photorelease experiment, a far red LED (Mightex Company, <NUM>, <NUM> mW/cm<NUM>) as excitation light source was used. <CHM>
Compounds <NUM>, <NUM>, Cou-C were synthesized according to the previous synthesis protocols<NUM>-<NUM>.

BDP-F: Under Ar atmosphere, compound <NUM> (<NUM>, <NUM> mmol), <NUM>-ethynyl-<NUM>-Octyl-fluorene∼<NUM> (<NUM>, <NUM> mmol), Pd(PPh<NUM>)<NUM>Cl<NUM> (<NUM>, <NUM> mmol), PPh<NUM> (<NUM>, <NUM> mmol), and CuI (<NUM>, <NUM> mmol) were dissolved in a mixed solvent of THF/N-ethyldiisopropylamine (<NUM>/<NUM>), and the flask was degassed many times by freezer-pump way. The mixture was heated at <NUM> for <NUM>. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (silica gel, hexane/CH<NUM>Cl<NUM>, <NUM>:<NUM>, v/v). The dark blue band was collected, and evaporation of solvent gave a black solid (<NUM>, <NUM> %). <NUM>H-NMR (<NUM>, CDCl<NUM>): δ = <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> ppm (s, <NUM>). <NUM>C-NMR (<NUM>, CDCl<NUM>): δ = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> ppm. ESI-HRMS (C<NUM>H<NUM>B<NUM>F<NUM>IN<NUM> + H+): calcd m/z = <NUM>; found m/z = <NUM>. FT-IR (KBr, cm-<NUM>): v = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. Molar extinction coefficients (<NUM>, ε = <NUM>×<NUM><NUM>M-<NUM> cm-<NUM>), HPLC (C<NUM> reverse column, eluent: CH<NUM>CN containing <NUM> % TFA) retention time <NUM>.

PEA: <NUM>-bromoanthracene (<NUM> mmol, <NUM>), phenylacetylene (<NUM> mmol, <NUM>) were dissolved in TEA and THF (<NUM>, <NUM>/<NUM>, v/v). The solution was degassed <NUM> times and Pd(PPh<NUM>)Cl<NUM> (<NUM> mmol, <NUM>), PPh<NUM> (<NUM> mmol, <NUM>) and CuI (<NUM> mmol, <NUM>) were added. The reaction was heated to <NUM> for <NUM>. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (silica gel, hexane/CH<NUM>Cl<NUM>, <NUM>:<NUM>, v/v). The yellow band was collected, and evaporation of solvent gave a black solid (<NUM>, <NUM> %). <NUM>H-NMR (<NUM>, CDCl<NUM>): δ = <NUM> (<NUM>, d, J =<NUM>), <NUM> (s, <NUM>), <NUM> (<NUM>, d, J = <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> ppm (m, <NUM>). <NUM>C-NMR (<NUM>, CDCl<NUM>): δ= <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>,<NUM>, <NUM>, <NUM>,<NUM>, <NUM> ppm. ESI-HRMS (C<NUM>H<NUM> + H+): calcd m/z = <NUM>; found m/z = <NUM>. FT-IR (KBr, cm-<NUM>): v = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. Molar extinction coefficients (<NUM>/<NUM>, ε = <NUM>×<NUM><NUM>/<NUM>×<NUM><NUM>M-<NUM> cm-<NUM>) HPLC (C<NUM> reverse column, eluent: CH<NUM>CN containing <NUM> % TFA) retention time <NUM>.

Diode pumped solid-state laser (<NUM>, continues wave, CW) was used for the upconversion. The diameter of the laser spot is <NUM>. For the upconversion experiments, the mixed solution of the BDP-F (sensitizer) and PEA (emitter) was degassed for at least <NUM>. Then the solution was excited with a laser. The upconverted fluorescence of PEA was recorded with spectrofluorometer.

The upconversion quantum yields (ΦUC) were determined with the prompt fluorescence of methyl blue as the standard (ΦF = <NUM>% in methanol). The upconversion quantum yields were calculated with the Eq. <NUM>, where ΦUC and Φstd stand for upconversion luminescence quantum yield of sample TTA-UC and fluorescence quantum yield of methyl blue, respectively. Aunk and Astd stand for absorbance of the TTA-UC and methyl blue, respectively. Iunk and Istd stand for integrated upconversion luminescence intensity of the TTA-UC and fluorescence intensity of methyl blue, respectively. ηunk and ηstd stand for the refractive index of water, The equation is multiplied by a factor of <NUM> to make the maximum quantum yield to be unity.

Triplet excited state lifetime of BDP-F measurement. The triplet excited state lifetime of BDP-F was measured on an LP <NUM> laser flash photolysis spectrometer (Edinburgh Instruments, U. ) and recorded on a Tektronix TDS 3012B oscilloscope. The lifetime values (by monitoring the decay trace of the transients) were obtained with the LP900 software. The sample in flash photolysis experiments was deaerated with argon for ca. before measurement, and the argon gas flow was kept during the measurement.

Firstly, MSNs silica nanoparticles were synthesized according to following steps. CTAB (<NUM>, <NUM> mmol) was dissolved in <NUM> of DI water. Sodium hydroxide aqueous solution (<NUM>, <NUM>) was introduced to the CTAB solution, and the temperature of the mixture was adjusted to <NUM>. TEOS (<NUM>, <NUM> mmol) was added dropwise to the surfactant solution under vigorous stirring. The mixture was allowed to react for <NUM> to give a white precipitate. This solid crude product was filtered, washed with deionized water and methanol, and dried in air to yield the as-synthesized mesoporous silica nanoparticles (denoted as MSN). To remove the surfactant template (CTAB), <NUM> of the as-synthesized MSN was refluxed for <NUM> in a methanolic solution of <NUM> of HCl (<NUM>%) in <NUM> of methanol. The resulting material was filtered and extensively washed with deionized water and methanol. The filter was dried under vacuum for <NUM> at room temperture.

Next, TTA-MSNs were prepared dependence on the following steps. MSNs (<NUM>) were dispersed <NUM> round flask in of BDP-F (<NUM>), PEA (<NUM>) and methyl oleate (<NUM>) in THF (<NUM>). The mixture solution was stirred until organic solvent evaporation (about <NUM>) at room temperature in the dark condition. And then <NUM> PBS buffer was added. The mixture was ultrasonic shocked for <NUM>. to make the nanoparticles dispersed in the PBS buffer. Then the BDP-F (sensitizer) and PEA (emitter)-loaded silica nanoparticles were low speed centrifuged (<NUM> rpm/min) for <NUM>. The supernatant was collected and then extracted using dichloromethane (DCM). The DCM solvent containing BDP-F and PEA was used to measure sensitizer and emitter loading by collecting UV-vis absorption spectra using a molar absorption coefficient of <NUM>-<NUM>cm-<NUM> with λmax = <NUM> for BDP-F, <NUM>-<NUM>cm-<NUM> with λmax = <NUM> for PEA. Sensitizer and emitter loading were calculated using the following equation: <MAT>.

The entrapment efficiency of BDP-F is <NUM>%, the entrapment efficiency of PEA is <NUM>%.

The precipitate containing sensitizer and emitter nanoparticles (TTA-MESNs) were collected and then dried (<NUM>) in the vacuum condition for <NUM> in the dark condition. At last, the dried TTA-MSNs was dispersed in PBS buffer by using ultrasonic shock for <NUM>. , the concentration of TTA-MSNs is <NUM>/mL. The size of the TTA- MSNs was measured by DLS in an aqueous suspension at <NUM>/mL of MSN in DI water, laser wavelength is <NUM>.

Cou-C (<NUM>), TTA-MSNs (<NUM>) and pluronic F-<NUM> (<NUM>) were dissolved in THF/toluene (<NUM>/<NUM>, v/v, <NUM>). The organic solvents were dried in the vacuum for <NUM> at <NUM> in the dark condition (note: all organic solvents should be removed). Then <NUM> PBS buffer was added. The mixture was stirred for <NUM> (<NUM> rpm/min) in the dark condition to make sure the solid dispersion. The mixture solution was low speed centrifuged (<NUM> rpm/min) for <NUM>. to remove the big size nanocapsule. The supernatant (TTA-CS) were carefully collected. And then the supernatant was filtrated with <NUM> membrane to obtain sterile nanocapsule. Finally, the TTA-CS was stored at <NUM> refrigerator.

The precipitate sample was extracted with <NUM> DCM. And then absorbance of Cou-C was measured to calculate the entrapment efficiency.

The entrapment efficiency of Cou-C is <NUM> %.

Far-red LED photocleave drug release of TTA-CS in solution. We found that the fluorescence of Cou-C reduced along with chlorambucil photoreleasing process at <NUM>. Based on the property, the photocontrollable chlorambucil releasing process also was monitored by measured the fluorescence spectra of Cou-C.

Human cervical carcinoma (HeLa cell lines) and mice breast cancer cells (4T1 cell lines) were cultured in Dulbecco's modified Eagle's medium (DMEM) containing <NUM>% fetal bovine serum (FBS), <NUM>µg mL-<NUM> streptomycin and <NUM> U mL-<NUM> penicillin at <NUM> in a humidified incubator containing <NUM>% CO<NUM> and <NUM>% air. The medium was replenished every other day and the cells were subculture after reaching confluence.

We seeded Hela or 4T1 cells at a density of <NUM> on the <NUM> well plates. After <NUM>, The cells were then incubated with <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>µg/mL of TTA-CS and control group (TTA-MSNs) in cell culture medium for <NUM> at <NUM> and <NUM>% CO<NUM>. Then the cells were irradiated by far red <NUM> LED for <NUM>. (<NUM> mW/cm<NUM>), photon fluene is <NUM> J/cm<NUM>. After irradiation the cells were again incubated for <NUM>. Then, <NUM>µL of <NUM> mL-<NUM> MTT solution in pH <NUM> PBS was added to each well. After <NUM> incubation, the medium containing unreacted MTT was removed carefully, and <NUM>µL DMSO was added to each well to dissolve the produced blue formazan. After <NUM>. , the optical density (OD) at a wavelength of <NUM> was measured with Bio-Rad microplate reader. The percentage of growth inhibition was calculated with Eq. <NUM>.

The cells (<NUM> × <NUM><NUM>) per well were seeded on confocal dish (<NUM>) and incubated in complete medium for <NUM> at <NUM>. The medium was then replaced with fresh culture medium containing TTA-CS (<NUM>µg/mL) to incubate for <NUM> at <NUM>. The cells were irradiated with a <NUM> far red light LED at a power of <NUM> mW/cm<NUM> for <NUM>. (photon fluene <NUM> J/cm<NUM>) and then culture another <NUM>. Afterward, the cells were stained with PI and calcein A. M according to the manufacturer's instruction. After <NUM>. , the solution was removed and PBS used to wash cells at least three times. The dead cells were visualized with a wide field fluorescence microscopy (<NUM>×oil objective). Excitation wavelength was <NUM>. Emission detection wavelength region was <NUM>-<NUM>. The living cells was also observed, the excitation wavelength was <NUM>, the emission was <NUM>-<NUM>.

The mice were subjected to four different treatments: Group <NUM>, PBS (<NUM>µL) and far red LED irradiation; Group <NUM>, intratumoral injection TTA-CS only (<NUM>µL, <NUM>/mL); Group <NUM>, intratumoral injection TTA-MSNs (<NUM>µL, <NUM>/mL) and far red LED irradiation; Ggroup <NUM>, intratumoral injection TTA-CS (<NUM>µL, <NUM>/mL) combined with exposure far red LED. After <NUM>, far red light LED (<NUM>) was performed on groups <NUM>, <NUM>, <NUM> at <NUM> mW cm-<NUM> for <NUM>.

(photon fluene <NUM> J/cm<NUM>). Two mice from each group were euthanized <NUM> d post-treatment, and tumor tissues of the above-mentioned treatment Groups <NUM>-<NUM> were harvested for histological study by H&E staining under a BX51 optical microscope (Olympus, Japan) in a blinded fashion by a pathologist. Different treatment groups were monitored by measuring the tumor size using a Vernier caliper for <NUM> d. Tumor size = width × width × length/ <NUM>. <CHM>
<CHM>.

<FIG> depicts an illustration of the preparation of TTA-CS, and TTA-UC mediated prodrug activation.

Applicant's disclosure is described herein in preferred embodiments with reference to the Figures, in which like numbers represent the same or similar elements. Reference throughout this specification to "one embodiment," "an embodiment," or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment," "in an embodiment," and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

The described features, structures, or characteristics of Applicant's disclosure may be combined in any suitable manner in one or more embodiments. In the description, herein, numerous specific details are recited to provide a thorough understanding of embodiments of the invention. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the disclosure.

In this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference, unless the context clearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed.

Claim 1:
An upconversion composition, comprising an organic triplet photosensitizer molecule and an organic emitter molecule, wherein the composition is characterized by an upconversion upon excitation in the red region of <NUM> to <NUM> or far red region of <NUM> to <NUM> with an emission in the deep blue region of <NUM> to <NUM>, wherein each of the triplet photosensitizer and emitter molecules comprises no metallic elements, wherein the triplet photosensitizer molecule has the structural formula (I):
<CHM>
wherein
each of R<NUM> and R<NUM> is independently selected from the group consisting of: H, bromo, iodio, alkynyl, alkyl, alkenyl, azide, PEG, amino, carboxyl acid and hydroxyl;
R<NUM> is selected from the group consisting of: bromo and iodio;
R<NUM> is an arylethynyl group, optionally selected from the group consisting of: phenylethynyl, naphthalene ethynyl, carbazole ethynyl and fluorenyl ethynyl; and
each R<NUM> is independently selected from the group consisting of: H and alkyl, and wherein the organic emitter molecule is <NUM>-phenylacetylene anthracene.