Silver sulfide quantum dots and uses thereof

Abstract

The present invention is directed to compositions comprising the Ag2S quantum dots of the invention and to methods for use thereof, such as for the treatment and / or prevention a cell or tissue damage and / or a disease or condition in a subject associated therewith. Further, pharmaceutical or cosmetic compositions comprising Ag2S quantum dots of the invention, and articles (e.g. cosmetic / medical article) comprising same are also provided.

Description

SILVER SULFIDE QUANTUM DOTS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 536,522, titled “SILVER SULFIDE QUANTUM DOTS AND USES THEREOF”, filed on September 05, 2023. The content of the above document is incorporated by reference in its entirety as if fully set forth herein.FIELD OF THE INVENTION

[0002] The invention relates generally to the field of quantum dots and methods for using thereof such as for the treatment of a disease in a subject.BACKGROUND OF THE INVENTION

[0003] The natural ability of the human body to regenerate tissues and organs is limited. Hence, in cases of injury, disease, or degeneration, the body's ability to replace damaged cells and restore normal tissue function is often insufficient. This can lead to chronic health conditions, impaired quality of life, and even life-threatening situations. In nerve injuries, disruption of the neuronal network prevents motor and sensory signals from being transmitted, hence preventing basic functions. To restore nerve function, recover the damaged nerve, and recreation of a new neuronal network is required. This is achieved by the axonal growth of existing neurons. Thus, axonal growth is required for nerve regeneration. Additionally, enhancing cell proliferation has a huge potential in medicine due to its ability to facilitate the growth and repair of damaged or degenerated tissues. In the context of wound healing, these can promote the rapid proliferation of cells in the wound area, leading to expedited wound closure and reduced scar formation. Enhancing cell proliferation can also be used in treatments of bums, traumatic injuries, and radiation damage to the peripheral nervous system. In addition, it can assist in organ transplantation, enabling the generation of ample cell populations critical for successful engraftment.

[0004] Wound dressings are a traditional treatment for wound and tissue healing. They are typically in the form of gauze, foam, or hydrogel and have antibacterial properties. Some smart wound dressings also modified pH and glucose levels for better recovery. However, they are suitable only for external application over the skin and unsuitable for many body parts that experience high stretch stress such as joints and the neck, nor for deep wounds and tissue damage.

[0005] Alternative treatments include steroids in oral administration and local injections and hyperbaric oxygen therapy (HBOT) which have limited effectiveness.

[0006] Several methods use electric field stimulation to enhance cell axonal growth and tissue regeneration. Traditional techniques generating electric fields for therapeutic applications involve the implantation of electrical probes in the patient's body. These techniques include FDA-approved treatments such as electrode-based deep brain stimulation (DBS) and Vagus nerve stimulation (VNS).

[0007] Traditional techniques to enhance cells regeneration with electric fields use electric probes which are invasive, expensive, and may injure healthy tissues. In addition, to generate the required electric field, the implementation of a millimetric scale or bigger devices is required. Hence in many cases, the implant causes inflammation and infection and suffers from poor spatial and temporal precision mismatches between electrical probes and cellular networks.

[0008] Due to the mentioned limitations, electric field stimulation is limited in tissue regeneration. Sudden sensorineural hearing loss (SSNHL) is one example of a medical condition resulting from decreased nerve activity in which existing electric therapies are problematic because of the delicate ear tissue involved. SSNHL is a sudden condition characterized by acute hearing loss, that occurs within a few hours or less due to nerve damage. Tinnitus is also associated with these conditions. Current SSNHL treatment focuses on nerve regeneration to restore hearing. The treatments include steroids delivered orally and in multiple intratympanic injections administration and hyperbaric oxygen therapy (HBOT), with limited effectiveness. HBOT requires a lot of time and dedication from patients, including weeks of treatments, five times a week, about 2 hours a day. It is also expensive and causes ear pressure, which might be problematic for kids and some adults. Intratympanic steroid administration requires multiple harmful injections through the eardrum by trained doctors.

[0009] The effectiveness of those treatments is limited, in many cases, those treatments show no benefit or partial benefit. Thus, there is a great unmet need for efficient treatment of diseases associated with neuronal damage, such as SSNHL.SUMMARY OF THE INVENTION

[0010] In one aspect of the present invention, there is provided a composition comprising Ag2S quantum dots, each of the Ag2S quantum dots (QD) is bound to a plurality of ligands represented by Formula 1, including any salt thereof:, wherein: n is an integer, ranging between 2 and 5;X is O, S or NH;R1 is H, or represents one or more substituents selected from -OH, halogen, oxo, carbonyl, OR’, -NO2, -CN, -C0NH2, -CONR’2, -CNNR’2, -CSNR’2, -CONH-OH, -C0NH-NH2, -NHCOR’, -NHCSR’, -NHCNR, -NC(=O)OR’, -NC(=O)NR’, -NC(=S)OR’, - NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl-C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl-NR’2, C1-C6 alkyl- SR’, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -C02H, -CO2R’, -OCOR, -OCOR’, - OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclic alkyl, or a combination thereof as allowed by valency;R is H, or represents one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -NO2, -CN, -OR’, -NH2, carbonyl, -C0NH2, -CONR’2, -CNNR2, -CSNR2, -CONH-OH, -CONH- NH2, -NHCOR’, -NHCSR’, -NHCNR’, -NC(=O)OR’, -NC(=O)NR’, -NC(=S)OR’, - NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, hydroxy(Cl-C6 alkyl), hydroxy(Cl-C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), amino(Cl-C6 alkyl), -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -C02H, -CO2R’, -OCOR’, -OCOR’, -OC(=O)OR’, - OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, a heteroatom, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, or a combination thereof, wherein each R’ is independently selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl a heteroatom, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, or anycombination thereof, as allowed by valency; and the QD are characterized by an average particle size between about 8 and about 14nm.

[0011] In one embodiment, QD further comprise up to 5% Ni by weight.

[0012] In one embodiment, QD are characterized by a negative zeta potential.

[0013] In one embodiment, QD are water soluble or water dispersible up to a concentration of lOmg / ml.

[0014] In one embodiment, plurality of ligands are covalently attached to a surface of the QD.

[0015] In one embodiment, QD are characterized by an average particle size of about lOnm.

[0016] In one embodiment, the plurality of ligands are:, including any salt thereof.

[0017] In one embodiment, QD are characterized by an absorption maximum at a first wavelength range between about 380 and about 400 nm and by a second wavelength range between about 800 and about 810, and by an emission maximum at a wavelength range between about 840 and about 860.

[0018] In one embodiment, QD are characterized by monodispersed size distribution.

[0019] In one embodiment, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0020] In one embodiment, the pharmaceutical composition is for use in enhancement or induction of cell proliferation and / or cell regeneration in a subject in need thereof.

[0021] In one embodiment, the cell comprises a neuronal cell, an endothelial cell, an epithelial cell, a muscle cell, and a fibroblast, including any combination thereof.

[0022] In another aspect, there is provided a composition comprising Ag2S quantum dots, each of the Ag2S quantum dots (QD) is bound to a plurality of ligands represented by Formula 1, including any salt thereof:, wherein: n is an integer, ranging between 2 and 5; X isO, S or NH; R1 is H, or represents one or more substituents selected from -OH, halogen, oxo, carbonyl, OR’, -N02, -CN, -C0NH2, -CONR’2, -CNNR’2, -CSNR’2, -CONH-OH, -C0NH-NH2, -NHCOR’, -NHCSR’, -NHCNR, -NC(=0)0R’, -NC(=0)NR’, - NC(=S)OR’, -NC(=S)NR’, -S02R’, -SOR’, -SR’, -S020R’, -SO2N(R’)2, -NHNR’2, - NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), - N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl- C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl-NR’2, C1-C6 alkyl-SR’, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -C02H, -C02R’, -OCOR, - OCOR’, -OC(=O)OR’, -0C(=0)NR’, -OC(=S)OR’, -OC(=S)NR’, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclic alkyl, or a combination thereof as allowed by valency; R is H, or represents one or more substituents selected from Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, halo, -N02, -CN, -OR’, -NH2, carbonyl, -C0NH2, -CONR’2, -CNNR2, -CSNR2, -CONH-OH, -CONH- NH2, -NHCOR’, -NHCSR’, -NHCNR’, -NC(=0)0R’, -NC(=0)NR’, -NC(=S)OR’, - NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, -NH(Ci- Ce alkyl), -N(CI-C6 alkyl)2, hydroxy(Ci-C6 alkyl), hydroxy(Ci-C6 alkoxy), alkoxy(Ci-C6 alkyl), alkoxy(Ci-C6 alkoxy), amino(Ci-C6 alkyl), -C0NH(CI-C6 alkyl), -C0N(CI-C6 alkyl)2, -CO2H, -CO2R’, -OCOR’, -OCOR’, -OC(=O)OR’, -0C(=0)NR’, -OC(=S)OR’, -OC(=S)NR’, a heteroatom, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, or a combination thereof, wherein each R’ is independently selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl a heteroatom, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, or any combination thereof, as allowed by valency.

[0023] In one embodiment, the QD are characterized by an average particle size below lOnm, as determined based on TEM analysis. In one embodiment, the QD are characterized by an average particle size between about 8 and about lOnm. In one embodiment, the QD are characterized by an average particle size between about 5 andabout 9nm. In one embodiment, the QD are characterized by an average particle size of about 7nm.

[0024] In one embodiment, the QD further comprise up to 5% of a dopant metal by weight of said QD.

[0025] In one embodiment, the said dopant metal is selected from the group consisting of Nickel (Ni), Copper (Cu), Iron (Fe), Zinc (Zn), Manganese (Mn), Cobalt (Co), Silver (Ag), Gold (Au), Cadmium (Cd), Lead (Pb), and Platinum (Pt), including any combination thereof.

[0026] In one embodiment, the pharmaceutical composition is for use in for use in at least one of: (i) enhancement and / or induction of cell proliferation; (ii) enhancement and / or induction of cell regeneration; (iii) promoting engraftment of a transplanted tissue.

[0027] In one embodiment, the cell comprises a neuronal cell, an endothelial cell, an epithelial cell, a muscle cell, and a fibroblast, including any combination thereof.

[0028] In one embodiment, the cell is the neuronal cell and wherein said cell regeneration comprises increasing axonal length and / or neuronal branching.

[0029] In one embodiment, the neuronal cell is a degenerated neuronal cell comprising at least one degenerated axon; and wherein increasing is by at least 10%, compared to an untreated degenerated neuronal cell.

[0030] In another aspect, there is provided a method for treating a disease or a disorder in a subject, comprising administering to the subject a therapeutically effective amount of composition of the invention, thereby treating the disease; wherein the administering further comprises excitation of the QD at a suitable wavelength.

[0031] In one embodiment, administering is by systemic administration.

[0032] In one embodiment, administering comprises intravenous, intramuscular, subcutaneous, intratympanic or intradermal administration.

[0033] In one embodiment, the disease or the disorder is associated with neuronal damage, cell transplantation, skin tissue damage, or any combination thereof.

[0034] In one embodiment, the disease or the disorder is a neurodegenerative disease. In one embodiment, the disease or the disorder is Sudden sensorineural hearing loss (SSNHL).

[0035] In one embodiment, the excitation comprises light irradiation of said subject; and wherein said suitable wavelength is between about 790 and about 830nm.

[0036] In one embodiment, the light irradiation is performed for a time period between 1 and 200 minutes.

[0037] In one embodiment, the light irradiation comprises a light radiation dose ranging between 0.05 and 5mw / cm2.

[0038] In another aspect, there is provided a cosmetic composition comprising the composition of the invention and a cosmetically acceptable carrier.

[0039] In another aspect, there is provided an article comprising the pharmaceutical composition of the invention or the cosmetic composition of the invention, and further comprising instructions for activating the QD via light irradiation at a wavelength ranging between 380 and 420nm or between 780 and 820nm.

[0040] In one embodiment, a concentration of the QD within the pharmaceutical composition is between 0.01-200 ug / ml.

[0041] In one embodiment, the article is in a form of: injectable composition, gel, ointment, wound dressing or patch.

[0042] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0043] Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figures 1A-1C are bar graphs demonstrating the integration of Ag2S 3% Ni QDs with HEK293. Ag2S 3%Ni QDs Toxicity assay with HEK293 exposed to the QDs for 24 hr in the dark (1A). Enhancement in cell viability using Ag2S 3%Ni dopping( on the expance of Ag) QDs illuminated with 810nm light in HEK293 cells (IB). (1C) is a bar graph demonstrating viability of a rat dorsal root ganglions (DRG) cells incubated with lOpg / ml QDs for 24hr, with and without NIR light illumination. All measured valueswere normalized to the average value of the untreated group of cells without QDs in the dark.

[0045] Figures 2A-2L are immunofluorescence microscopy images of HEK293 cells exposed to 30sec NIR light (2G-2L) or grew in the dark (2A-2F). Figures 2D-2F and 2J- 2L are images of HEK293 cells incubated with Ag2S 3% Ni QDs. Figures 2A-2C and 2G- 21 are images of HEK293 cells without Ag2S 3% Ni QDs (i.e. control). Cells nuclei were stained with Hoechst stain (blue color in the images); cells cytoplasm was stained with Calcein dye (green color in the images). The cells were imaged 20 hours after illumination using the Lionheart FX automated microscope.

[0046] Figure 3 is a scheme providing an illustration of the synthesis route and the structure of the synthesized Ag2S QD decorated with thioglycolic acid (TGA) or 3 mercaptopropionic acid (MPA) ligands.

[0047] Figures 4A-4C are graphs and image presenting Ag2S QDs characterization. UV- VIS absorbance spectrum, emission spectrum, with 380nm excitation and excitation peak with 850nm emission. All spectrums were created using a TECAN m200 plate reader (4A). Scanning transmission electron microscopy (STEM) image of the as synthesized QDs (4B). Size distribution (and mean particle size) of the synthesized QDs, estimated based on the TEM image (4C).

[0048] Figures 5A-5C are graphs and images presenting QDs Photocatalytic activity. Comparison between QDs activity with and without Ni doping (5A), and Ni doped QDs illuminate with 810nm and 400nm (5B). MB photocatalytic activity of QDs decorated with MPA and TGA ligands, under 810nm 38mw LED light illumination. (* PV<0.033, ****PV<0.0001) (5C).

[0049] Figures 6A-6E are images showing (6A) scanning transmission electron microscopy (STEM) image and (6B-6E) STEM Energy-dispersive X-ray (EDX) of the QDs presenting the QDs atomic composition.

[0050] Figure 7 is a scheme showing photoelectric mechanism of the QDs. QDs electron-hole generation and electron transfer mechanisms illustration. Band gap calculated through Tauc Plot.

[0051] Figures 8A-8B are graphs showing cell viability experiments. (8 A) Viability of SHSY-5Y cells incubated with the QDs in various concentrations for 7 days. All measured values were normalized to the average value of untreated cells with no QDs. (8B) Viability of SHSY-5Y cells incubated with lOpg / ml QDs for 24hr and illuminatedwith NIR light. All measured values were normalized to the average value of cells illuminated for the same time without the QDs.

[0052] Figures 9A-9D. Ag2S 3% Ni QDs induce cell differentiation, axonal growth, and neuronal network generation in SHSY-5Y neurons, with Isec on 4sec off 810nm LED illumination in various durations, with and without lOpg / ml QDs. Fig. 9A shows Immunofluorescence images. Figs. 9B-9C are bar graphs showing branching (9B) and axon length (9C) assessment based on microscopy image analysis with (n>500). Fig. 9D is a bar graph showing neuronal protein levels (Tyrosine Hydroxylase (TH) and anti Q3 tubulin (|3T) as detected by Flow Cytometry. (* PV<0.033, **PV<0.0021, ****pv<0.0001).DETAILED DESCRIPTION OF THE INVENTION

[0053] In one aspect of the invention, there is provided a composition comprising Ag2S quantum dots, each of the Ag2S quantum dots (QD) is bound to a plurality of ligands represented by Formula 1, including any salt thereof:, wherein n is an integer, ranging between 2 and 5;X is O, S or NH; Rl is H, or represents one or more substituents selected from -OH, halogen, oxo, carbonyl, OR’, -NO2, -CN, -CONH2, -CONR’2, -CNNR’2, -CSNR’2, - CONH-OH, -CONH-NH2, -NHCOR’, -NHCSR’, -NHCNR, -NC(=O)OR’, - NC(=O)NR’, -NC(=S)OR’, -NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl-C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl- NR’2, C1-C6 alkyl-SR’, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R’, -OCOR, -OCOR’, -OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclic alkyl, or a combination thereof as allowed by valency; R is H, or represents one or more substituents selected from Ci-Ce alkyl, Ci-Ce alkoxy, Ci-C6haloalkoxy, halo, -NO2, -CN, -OR’, -NH2,carbonyl, -CONH2, -CONR’2, -CNNR2, -CSNR2, -CONH-OH, -CONH- NH2, -NHCOR’, -NHCSR’, -NHCNR’, -NC(=O)OR’, -NC(=O)NR’, -NC(=S)OR’, - NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, -NH(CI-C6alkyl), -N(CI-C6 alkyl)2, hydroxy(Ci-C6 alkyl), hydroxy(Ci-C6 alkoxy), alkoxy(Ci-C6 alkyl), alkoxy(Ci-C6 alkoxy), amino(Ci-C6 alkyl), -CONH(CI-C6 alkyl), -CON(CI-C6 alkyl)2, -CO2H, -CO2R’, -OCOR’, -OCOR’, -OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, - OC(=S)NR’, a heteroatom, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, or a combination thereof, wherein each R’ is independently selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl a heteroatom, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, or any combination thereof, as allowed by valency; and the QD are characterized by an average particle size below 10 nm.

[0054] In another aspect of the invention, there is provided a composition comprising water soluble or water dispersible quantum dots, each of the water soluble or water dispersible quantum dots (WQD) is bound to a plurality of ligands, wherein the plurality of ligands are water soluble molecules, optionally comprising a polar or a polarizable functional group (e.g. carboxy, amino, nitro, sulfonate, phosphate, etc.). In some embodiments, the WQD are metal / metalloid sulfide based quantum dots, and have an excitation wavelength at a near IR range (e.g. between 360 and 390nm, or between 700 and 900 nm, more specifically between 790 and 820 nm); and wherein the WQD are biocompatible (e.g. biocompatible at a therapeutically effective concentration of the WQD). In some embodiments, the WQD are metal / metalloid sulfide based quantum dots, and have an excitation wavelength at a near IR range (e.g. between 360 and 390nm, or between 700 and 900 nm, more specifically between 790 and 820 nm); wherein the WQD are water soluble or water dispersible; wherein the WQD are biocompatible (e.g. biocompatible at a therapeutically effective concentration of the WQD); and wherein the WQD are selected from Ag2S, Bi2S3 and InP / ZnS quantum dots, including any combination thereof. In some embodiments, the WQD are further characterized by a similar therapeutic activity (i.e. a similar potency and / or similar indications), as disclosed below for Ag2S quantum dots. In some embodiments, additional physicochemical properties of the WQD (e.g. particle size, metal doping, ligands, PDI, zeta potential) as well as specific therapeutic use thereof, are as disclosed below for QD (i.e. Ag2S quantum dots).

[0055] In some embodiments, the plurality of ligands are represented by Formula I, including any salt thereof:, wherein:A represents an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted heteroalkenyl, or an optionally substituted alkenyl, wherein any one of the above is between 2 and 10, between 2 and 8 between 2 and 6 between 2 and 5 carbon atoms long;G represents one or more polar or polarizable functional group(s) selected from -OH, oxo, carbonyl, -NO2, -CN, -C0NH2, -C0NR’2, -CNNR’2, -CSNR’2, -C0NH-0H, - C0NH-NH2, -NHC0R’, -NHCSR’, -NHCNR, -NC(=0)0R’, -NC(=0)NR’, - NC(=S)0R’, -NC(=S)NR’, -S02R’, -SOR’, -SR’, -S020R’, -SO2N(R’)2, -NHNR’2, - NNR’, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CONH(C1-C6 alkyl), -CON(C1-C6 alky 1)2, -C02H, -C02R’, -0C0R, -0C0R’, -0C(=0)0R’, -0C(=0)NR’, -OC(=S)OR’, -0C(=S)NR’, or a combination thereof as allowed by valency; wherein each R’ is independently selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl a heteroatom, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, or any combination thereof, as allowed by valency.

[0056] The terms “water soluble” or “water dispersible” encompass a stable aqueous solution / dispersion containing the quantum dots at a concentration being at least a therapeutically effective concentration of the corresponding quantum dot. The term “stable” encompasses that between 80 and 100% of the initial amount of quantum dots within the aqueous solution / dispersion (i.e. an amount immediately after the preparation of the solution / dispersion) remain dissolved / dispersed within the aqueous solution / dispersion for a time period of at least Ih, at least 2h, at least lOh, or at least 24h, including any range between. The term “dissolved”, refers to an aqueous composition being devoid of particles (aggregates) detectable by DLS. The term “dispersed”, refers to the ability of quantum dots to be present in the solution without precipitating therefrom or without forming aggregates. Aggregates formation can be determined by DLS or TEM microscopy.

[0057] In some embodiments, the quantum dots are soluble / dispersible in an aqueous composition refers to a concentration up to 10 mg / ml, up to 5 mg / ml, up to 1 mg / ml, up to 0.5 mg / ml, or between lOng / ml and lOmg / ml, between Ing / ml and 5mg / ml, between lOng / ml and Img / ml, between lOng / ml and 500ug / ml, between lOng / ml and 300ug / ml, between lOng / ml and 400ug / ml, between lOng / ml and 200ug / ml, between lOng / ml and250ug / ml, between lOng / ml and 15Oug / ml, between lOng / ml and lOOug / ml, including any range between. In some embodiments, the upper solubility / dispersibility threshold refers to a concentration of the QD in an aqueous salt solution or aqueous buffer, as opposed to pure water. The term “aqueous composition” encompasses an aqueous solvent being substantially (i.e. up to a concentration of 1%, of 0.5%, or up to a concentration of 0.1%w / w) or completely devoid of an organic solvent (i.e. non-aqueous solvent). The aqueous solvent encompasses water (e.g. distilled water, such as DDW) or an aqueous salt solution comprising at least one salt or ion specie (e.g. a buffer, NaCl, or any other pharmaceutically acceptable salt) dissolved therewithin.). The term “aqueous salt solution” may encompass an aqueous solution containing between 0.1 and 5%w / w of the total salt content.

[0058] In some embodiments, the average particle size of the quantum dots within the composition is below 14nm, below 13 nm, below 10 nm, between about 5 and about 9 nm, between about 6 and about 9 nm, between about 6 and about 8 nm, between about 7 and about 8 nm, between about 7 and about 9 nm, between about 8 and about 10 nm, between about 7 and about 10 nm, between about 7.2 and about 8 nm, between about 7.2 and about 10 nm, between about 6 and about 10 nm, between about 5 and about 8 nm, between about 6 and about 10 nm, between about 5 and about 7.2 nm, between about 6 and about 7.2 nm, between about 5 and about 6nm, between 8 and 14, between 8 and 13, between 8 and 12, between 9 and 12, between 9 and 15, between 8 and 13nm, including any range between. In some embodiments, the average particle size of the quantum dots (e.g. Ag2S or QD) is about lOnm. In some embodiments, the average particle size of the quantum dots (e.g. Ag2S or QD) is about 7nm.

[0059] In some embodiments, the QD of the invention are obtained by heating an Ag salt (e.g. AgNCh) with the ligand in an appropriate organic solvent (e.g. a glycol) at a temperature between about 90 and about 130°C, and by incubating the reaction mixture at a temperature about 145°C for a time period ranging between about 50 and about 70 min (e.g. about 60 min); wherein the ligand is represented by Formula I, wherein S atom is bound to hydrogen.

[0060] In some embodiments, the average particle size of the quantum dots (e.g. Ag2S or QD) is between about 5 and about 9 nm. The inventors have surprisingly observed that QDs with a particle size below about 5 nm didn’t exhibit any significant optoelectrical activity, as further mentioned in eth Examples section.

[0061] In some embodiments, the composition of the invention is characterized by a monodispersed size distribution of the quantum dots. In some embodiments, the composition of the invention is characterized by a monodispersed size distribution and by PDI of the quantum dots of between 0.01 and 0.3, including any range between. The average particle size and / or PDI, as used herein, refers to a particle size / PDI value as determined based on TEM image analysis.

[0062] In some embodiments, the QD are as disclosed above and are further characterized by a negative zeta potential. In some embodiments, the QD are characterized by a negative zeta potential, when measured at a pH between 6 and 8. In some embodiments, the negative zeta potential is between -1 and -lOmV, between -2 and -lOmV, between -2 and -5mV, between -1 and -5mV, including any range between.

[0063] In some embodiments, the ligands are represented by Formula 1, wherein R1 is H. In some embodiments, the ligands are represented by Formula 1, wherein R1 is H and n is 2 or 3. In some embodiments, X is O or S, and R is H. In some embodiments, the ligands are represented by Formula 1, wherein R1 is H and n is 2 or 3, X is O or S, and R is an optionally substituted Ci-Ce alkyl, or cycloalkyl.

[0064] In some embodiments, the ligands are represented by Formula 2:, wherein X is S or O; and wherein R is H, or represents one or more substituents selected from Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, halo, -NO2, -CN, -OR’, -NH2, carbonyl, -CONH2, -CONR’2, -CNNR2, -CSNR2, -CONH- OH, -CONH-NH2, -NHCOR’, -NHCSR’, -NHCNR’, -NC(=O)OR’, -NC(=O)NR’, - NC(=S)OR’, -NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, - NNR’, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, hydroxy(Ci-C6 alkyl), hydroxy(Ci-C6 alkoxy), alkoxy(Ci-C6 alkyl), alkoxy(Ci-C6 alkoxy), amino(Ci-C6 alkyl), -CONH(CI-C6 alkyl), -CON(CI-C6alkyl)2, -CO2H, -CO2R’, -OCOR’, -OCOR’, -OC(=O)OR’, - OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, a heteroatom, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, or a combination thereof. In some embodiments, the ligands are represented by Formula 2, wherein R is H.

[0065] In some embodiments, the ligands areincluding any salt thereof.

[0066] In some embodiments, the plurality of ligands have the same or different chemical structure(s). In some embodiments, the plurality of ligands are covalently bound to the QD. In some embodiments, the plurality of ligands are covalently bound via a metal-S bond. In some embodiments, the plurality of ligands are covalently bound to at least a portion of the outer surface of the QD. In some embodiments, the outer surface of each QD is decorated with the plurality of ligands. In some embodiments, the plurality of ligands form a layer or a shell, wherein the layer or shell at least partially encloses the core. In some embodiments, the core comprises or consists essentially of Ag2S.

[0067] In some embodiments, the Ag2S within the QD comprises or consists essentially of Ag2S in a crystalline state. In some embodiments, the Ag content of the QD is between 20 and 80at%, including any of the following sub-ranges: 20 to 30at%, 30 to 40at%, 40 to 50at%, 50 to 60at%, 60 to 70at%, and 70 to 80at%, optionally as determined by Energy- Dispersive X-ray Spectroscopy (EDX) or Atomic Absorption Spectroscopy.

[0068] In some embodiments, the weight portion of the ligands within the QD is between 0.00001 and 10%, is between 0.00001 and 1%, is between 0.0001 and 1%, is between 0.001 and 1%, is between 0.01 and 1%, is between 0.1 and 1%, including any range between.

[0069] In some embodiments, the QD further comprise up to 5%, up to 4%, up to 3% dopant metal (e.g. elemental state metal or a metal cation / salt) by weight (or at%). In some embodiments, the dopant metal is selected from the group consisting of Nickel (Ni), Copper (Cu), Iron (Fe), Zinc (Zn), Manganese (Mn), Cobalt (Co), Silver (Ag), Gold (Au), Cadmium (Cd), Lead (Pb), and Platinum (Pt), including any combination thereof. In some embodiments, the dopant metal is Ni.

[0070] In some embodiments, the QD are dopped by Ni. In some embodiments, the at% of Ni (also referred to herein as Ni content) within the QD is between 0.5 and 5, between 1 and 5, between 0.5 and 4, between 1 and 4%, including any range between. In some embodiments, the Ni content of the QD is about 3at%.

[0071] In some embodiments, the Ni content of the QD is between about 1 and 4%w / w, and the average particle size of the QD is about lOnm. In some embodiments, theQD / WQD consists essentially of the metal / metalloid sulfide QD (e.g. Ag2S QD) bound to the plurality of ligands and optionally of the dopant.

[0072] In some embodiments, the composition consists essentially of the QD / WQD disclosed above. In some embodiments, at least 80%, at least 90%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% by dry weight of the composition consists essentially of the QD / W QD disclosed above. In some embodiments, the QD / WQD disclosed above is the sole photocatalytic agent (or particle) of the composition of the invention.

[0073] In some embodiments, the QD are characterized by an absorption maximum at a first wavelength range between 380 and 420nm, between about 380 and about 420nm, or between about 380 and about 400nm, and by a second wavelength range between 780 and 820nm, between about 790 and 810nm, between 790 and 820 nm, between about 800 and about 820nm, between about 800 and about 810nm. In some embodiments, the QD are as disclosed above (e.g. particles size, zeta potential, Ni dopped) and are further characterized by at least one absorption maximum between about 800 and about 810nm. In some embodiments, the QD are characterized by at least one emission maximum at a wavelength range between about 840 and 860nm. In some embodiments, the QD are as disclosed above (e.g. particles size, zeta potential, Ni dopped) and are further characterized by at least one absorption maximum between about 800 and about 810nm and by at least one emission maximum at a wavelength range between about 840 and 860nm.

[0074] In some embodiments, the QD / WQD are photocatalytic nanoparticles. In some embodiments, the QD / WQD are characterized by optoelectrical activity. In some embodiments, the photocatalytic nanoparticles are configured to generate free electrons upon irradiation thereof with light at a wavelength ranging within the second wavelength range (also referred to herein as “optoelectrical activity”).

[0075] The photovoltaic effect is the direct conversion of light into electricity. In photocatalytic nanoparticles, a photon excites an electron from the valance band (VB) to the conduction band (CB) and generates charge separation and electron-hole pair (see Fig 7A). The energy gap between the VB and the CB is called the band gap.

[0076] In some embodiments, the band gap of the QD / WQD is between about 1 and about 1.5 eV, between about 1 and about 1.5 eV, between about 1 and about 1.5 eV, between about 1.1 and about 1.5 eV, between about 1.2 and about 1.5 eV, between about1.2 and about 1.4 eV, between 1.2 and 1.4 eV, about 1.3 eV, or 1.3eV, calculated from the QD / WQD absorbance spectra according to Tauc Plot method.

[0077] In some embodiments, the photocatalytic nanoparticles are configured to exhibit optoelectrical activity (ex-vivo, in-vivo, or in-vitro) upon illumination thereof with nearinfrared (NIR) light at a wavelength of about 810nm. In some embodiments, illumination is performed for a time period ranging at least between 0.01 and lOseconds, including any of the following sub-ranges: 0.01 to 0.1 seconds, 0.1 to 0.5 seconds, 0.5 to 1 second, 1 to 2 seconds, 2 to 3 seconds, 3 to 4 seconds, 4 to 5 seconds, 5 to 6 seconds, 6 to 8 seconds, and 8 to 10 seconds. In some embodiments, illumination is performed for a time period disclosed hereinbelow (see “irradiation time”).Pharmaceutical / cosmetic composition

[0078] In another aspect, there is provided a pharmaceutical composition, comprising the composition disclosed herein (QD or WQD-based composition) and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises one or more WQD (i.e. at least two quantum dot species having different chemical composition) of the invention and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of one or more quantum dots of the invention. In some embodiments, the pharmaceutical composition consists essentially of QD / WQD as the sole photocatalytic agent, and wherein the QD / W QD are characterized by an average particle size between about 5 and about 9nm, or about 7nm.

[0079] In some embodiments, the pharmaceutical composition consists essentially of the quantum dots of the invention and the pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition consists essentially of the quantum dots of the invention as the therapeutically active ingredient. In some embodiments, the pharmaceutical composition is devoid of additional therapeutically active ingredients. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the quantum dots of the invention.

[0080] As used herein, the term "consists essentially of" means that the composition, method, system, kit or article may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

[0081] In some embodiments, the pharmaceutical composition is an aqueous composition. In some embodiments, the aqueous composition is selected from an aqueous solution, aqueous dispersion, emulsion, or suspension.

[0082] In some embodiments, the pharmaceutical composition is for use in the treatment or prevention of a disease or a disorder, in a subject in need thereof. In some embodiments, the pharmaceutical composition is for use in the treatment of a disease / disorder or a condition associated with cell damage. In some embodiments, the pharmaceutical composition is for use in induction or enhancement of cell proliferation and / or cell regeneration in a subject in need thereof.

[0083] In some embodiments, the cell is a skin cell. In some embodiments, the cell is a neuronal cell. In some embodiments, the cell is any of endothelial cell, epithelial cell, muscle cell (e.g. smooth muscle cell), and a fibroblast. In some embodiments, the cell further encompasses a tissue. In some embodiments, the cell is characterized by impaired proliferation or growth rate, as compared to a normal cell of the same type. In some embodiments, the cell is a healthy cell in a harmed cell environment.

[0084] In some embodiments, the pharmaceutical composition is for use in induction or enhancement of proliferation and / or regeneration of a neuronal cell.

[0085] In some embodiments, regeneration of a neuronal cell comprises promoting or inducing axonal growth in the neuronal cell. In some embodiments, the neuronal cell is a degenerated neuronal cell comprising a degenerated axon. In some embodiments, the neuronal cell is a degenerated neuronal cell comprising a degenerated axon, and wherein promoting or inducing axonal growth refers to elongation of the degenerated axon.

[0086] A degenerated axon is an axon that has experienced structural and functional deterioration, often characterized by the breakdown of the axonal cytoskeleton, reduced axonal length, loss of myelin sheath, disruption of axonal transport, and impaired ability to transmit electrical signals.

[0087] A degenerated neuronal cell is a neuron that has undergone structural and functional deterioration, often characterized by the loss of axonal integrity, reduced synaptic connections, and impaired signal transmission. This degeneration can result from various factors, including injury, disease, or aging, leading to compromised neuronal function and connectivity within the nervous system.

[0088] In some embodiments, axonal growth comprises elongation of axon length by between 10 and 600%, including any of the following sub-ranges: 10 to 50%, 50 to 100%, 100 to 150%, 150 to 200%, 200 to 300%, 300 to 400%, 400 to 500%, and 500 to 600%.In some embodiments, the axon length is elongated by between 50 and 600%, including any of the following sub-ranges: 50 to 60%, 60 to 80%, 80 to 100%, 100 to 150%, 150 to 200%, 200 to 300%, 300 to 400%, 400 to 500%, and 500 to 600%. Elongation of axon length is determined relative to an average axon length (e.g. of degenerated axons) before promoting or inducing axonal growth by the composition of the invention. Elongation of axon length can be determined by immunofluorescence imaging and microscopy image analysis. Elongation of axon length refers to the elongation of the degenerated axon (e.g. restoration of the cytoskeleton), thereby restoring its length and function.

[0089] In some embodiments, axonal growth comprises increasing neuronal branching. Neuronal branching refers to developing of new branches or extensions, known as dendrites and axons, which enhance their ability to connect with other neurons and form complex neural networks. Neuronal branching can be determined by immunofluorescence imaging and microscopy image analysis, which involve staining the neurons with specific fluorescent markers and analyzing the images to quantify the number and length of branches. Neuronal branching is determined relative to an average number of branches within a nerve cell (e.g. of a degenerated nerve cell) before promoting or inducing neuronal branching by the composition of the invention. In some embodiments, increasing neuronal branching is by at least 20%, at least 50%, at least 70%, at least 30%, at least 100%, at least 200%, or between 20 and 200%, including any of the following sub-ranges: 20 to 50%, 50 to 70%, 70 to 100%, 100 to 150%, 150 to 200%, 20 to 40%, 40 to 60%, 60 to 80%, 80 to 100%, 100 to 120%, 120 to 140%, 140 to 160%, 160 to 180%, and 180 to 200%. Neuronal branching and axonal growth can be determined invivo by the restoration of a lost sensorial or motorial activity.

[0090] In another aspect, there is provided a method for optoelectrical stimulation of neurons in a subject, comprising administering the pharmaceutical composition to the subject comprising the QD / W QD, and illuminating the administered QD / W QD with light (e.g. NIR light) at a wavelength suitable for inducing optoelectrical activity of the QD, promoting or inducing axonal growth within the subject. In some embodiments, the method results in generation of free electrons within the subject, wherein the free electrons induce stimulation of neurons. In some embodiments, the stimulation is an optoelectrical stimulation. In some embodiments, the optoelectrical stimulation promotes axonal growth / neuronal branching. In some embodiments, the optoelectrical stimulation / generation of free electrons induces production of axonal growth-associated protein(s). Exemplary axonal growth-associated protein include but are not limited toTyrosine Hydroxylase (TH), P3 tubulin (PT), Growth Associated Protein 43 (GAP-43), Microtubule-Associated Protein 2 (MAP2), Neurofilament Light Chain (NFL), Neurofilament Medium Chain (NFM), Neurofilament Heavy Chain (NFH), Synapsin I, Brain-Derived Neurotrophic Factor (BDNF), Neuronal Growth Factor (NGF), Doublecortin (DCX), and Vimentin.

[0091] In some embodiments, the method is for inducing / enhancing neuronal network formation, neuronal branching and / or axonal growth through optoelectrical stimulation.

[0092] In some embodiments, the method is for any one of: stimulating cell proliferation, tissue regeneration, and promoting the engraftment and regeneration of transplanted tissues.

[0093] In some embodiments, the neuronal cells are selected from Sensory Neurons (e.g., Olfactory Neurons, Retinal Ganglion Cells, Primary Dorsal Root Ganglion (DRG) Neurons), Motor Neurons (including but not limited to Upper Motor Neurons and Lower Motor Neurons), Interneurons (including but not limited to Pyramidal Neurons, Granule Cells, and Purkinje Cells), and Autonomic Neurons (including but not limited to Sympathetic Neurons and Parasympathetic Neurons).

[0094] In some embodiments, the neuronal cells are selected from Neuroblastoma Cells, Primary Dorsal Root Ganglion (DRG) Neurons, Cortical Neurons, Hippocampal Neurons, Motor Neurons, Sensory Neurons, Sympathetic Neurons, Parasympathetic Neurons, Purkinje Cells, Retinal Ganglion Cells, Olfactory Neurons, Interneurons, Pyramidal Neurons, Granule Cells, Cholinergic Neurons, Dopaminergic Neurons, GABAergic Neurons, Glutamatergic Neurons, Serotonergic Neurons, and Noradrenergic Neurons. In some embodiments, the pharmaceutical composition is for use in the treatment of neuronal cell damage, and / or a disease or condition associated therewith.

[0095] In some embodiments, the pharmaceutical composition is for use in induction or enhancement of wound healing (e.g. healing of a tissue damage, such as skin bum, skin wound, or a tissue damage associated with organ transplantation).

[0096] In some embodiments, the pharmaceutical composition is for use in the treatment of a disease associated with a neuronal damage. In some embodiments, the neuronal damage comprises axon degeneration. In some embodiments, the pharmaceutical composition is for use in the treatment of a disease associated with axon degeneration. In some embodiments, disease associated with axon degeneration comprises central nervous system (CNS) disease (e.g. amyotrophic lateral sclerosis (ALS), multiple sclerosis, and Parkinson's disease), peripheral nervous system (PNS) disorder (e.g. chemotherapy-induced, diabetic, and inherited neuropathy), ocular disorder (e.g. glaucoma), including any combination thereof. In some embodiments, disease associated with axon degeneration comprises Alzheimer's disease, Huntington's disease, Spinal muscular atrophy (SMA), Charcot-Marie-Tooth disease, Guillain-Barre syndrome, Chronic inflammatory demyelinating polyneuropathy (CIDP), Optic neuritis, Retinitis pigmentosa, Friedreich's ataxia, Hereditary spastic paraplegia, Progressive supranuclear palsy (PSP), Primary lateral sclerosis (PLS), Neuromyelitis optica (NMO), Leber's hereditary optic neuropathy (LHON), Peripheral neuropathy due to vitamin deficiencies (e.g., B12 deficiency), Traumatic brain injury (TBI), Spinal cord injury (SCI), Ischemic optic neuropathy, Wallerian degeneration, including any combination thereof.

[0097] In some embodiments, the disease associated with a neuronal damage is a neurodegenerative disease. In some embodiments, the pharmaceutical composition is for use in the treatment or prevention of a neurodegenerative disease. In some embodiments, the neurodegenerative disorder is selected from the group comprising: Alzheimer's disease, multiple sclerosis, dementia, Parkinson's disease, Huntington's disease, Down syndrome, Amyotrophic lateral sclerosis (ALS), prion disease, Spinal muscular atrophy (SMA), Charcot-Marie-Tooth disease, Guillain-Barre syndrome, Chronic inflammatory demyelinating polyneuropathy (CIDP), Optic neuritis, Retinitis pigmentosa, Friedreich's ataxia, Hereditary spastic paraplegia, Progressive supranuclear palsy (PSP), Primary lateral sclerosis (PLS), Neuromyelitis optica (NMO), Leber's hereditary optic neuropathy (LHON), Peripheral neuropathy due to vitamin deficiencies (e.g., B12 deficiency), Traumatic brain injury (TBI), Spinal cord injury (SCI), Ischemic optic neuropathy, and Wallerian degeneration, or any combination thereof.

[0098] In some embodiments, illuminating the QD / WQD is performed for a time period (also used herein as “irradiation time”) ranging between 1 and 200 minutes, including any of the following sub-ranges: 1 to 10 minutes, 10 to 20 minutes, 20 to 30 minutes, 30 to 40 minutes, 40 to 50 minutes, 50 to 60 minutes, 60 to 70 minutes, 70 to 80 minutes, 80 to 90 minutes, 90 to 100 minutes, 100 to 150 minutes, and 150 to 200 minutes.

[0099] In some embodiments, the wavelength suitable for inducing optoelectrical activity of the QD is between 780 and 850nm, between 800 and 850nm, between 780 and 830nm, between 780 and 820nm, between 780 and 810nm, between 800 and 830nm, between 800 and 820nm, including any range between.

[0100] In some embodiments, illuminating the QD / WQD is performed at a light radiation dose ranging between 0.05 and 5mw / cm2, including any of the following sub-ranges: 0.05 to 0.1mw / cm2, 0.1 to 0.3mw / cm2, 0.1 to 0.4mw / cm2, 0.08 to 0.4mw / cm2, 0.1 to 0.5mw / cm2, 0.5 to lmw / cm2, 0.5 to 3mw / cm2, 0.5 to 5mw / cm2, 1 to 2mw / cm2, 2 to 3mw / cm2, 3 to 4mw / cm2, and 4 to 5mw / cm2.

[0101] In some embodiments, the irradiation time is sufficient for inducing enhancing optoelectrical stimulation. In some embodiments, the irradiation time is sufficient for inducing a biological effect selected from any one of: neuronal network formation, neuronal branching and axonal growth within the subject.

[0102] In some embodiments, illuminating the QD / W QD is performed in a continuous mode, i.e. the light source emits light continuously without interruption for the entire duration of the irradiation period.

[0103] In some embodiments, illuminating the QD / WQD is performed in a pulsed mode, i.e., the light source emits light in regular intervals of “on” and “off cycles” (each cycle may range between 1-60 second) throughout the duration of the irradiation period. Without being bound to any particular theory, it is postulated that pulsed illumination can help to reduce potential thermal effects and allow for controlled delivery of light energy to the QDs / WQDs. In some embodiments, illuminating the QD / WQD is performed in a pulsed mode, i.e., the light source emits light in regular intervals of on and off cycles throughout the duration of the irradiation period, including any of the following subranges: 1 to 10 seconds, 10 to 20 seconds, 20 to 30 seconds, 30 to 40 seconds, 40 to 50 seconds, and 50 to 60 seconds.

[0104] The biological effect can be assessed in-vivo after a time period ranging between 1 day and 1 month post illumination, including any of the following sub-ranges: 1 to 3 days, 3 to 7 days, 7 to 10 days, 10 to 14 days, 14 to 21 days, and 21 to 30 days. The biological effect can be assessed in-vivo using suitable methods such as immunofluorescence imaging, microscopy image analysis, flow cytometry (i.e. in a sample derived from the subject. Alternative methods comprise electrophysiological recordings, and behavioral assays such as sensorial or motorial activity restoration.

[0105] In another aspect, there is provided a cosmetic composition, comprising the composition disclosed herein (QD or WQD-based composition) and a cosmetically acceptable carrier. In some embodiments, the cosmetic composition comprises a cosmetically effective amount of the quantum dots disclosed herein.

[0106] In some embodiments, the cosmetic composition is selected from a solid formulation, a liquid formulation (e.g. an aqueous formulation), a gel, an emulsion, a cream, a foam, or any combination thereof. In some embodiments, the cosmeticcomposition further comprises an additive, such as thickener, fragrance, a buffering agent, a stabilizer, an antioxidant, etc. In some embodiments, the cosmetically acceptable carrier comprises a surfactant. In some embodiments, the surfactant is selected from an anionic surfactant, a cationic surfactant, and a non-ionic surfactant, including any combination thereof.

[0107] Non-limiting examples of surfactants include but are not limited to: non-ionic surfactants (e.g., glyceryl monolinoleate glyceryl monooleate, glyceryl monostearate lanolin alcohols, lecithin mono- and di-glycerides poloxamer polyoxyethylene 50 stearate, and sorbitan trioleate stearic acid), anionic surfactants (e.g. pharmaceutically, cosmeceutically and / or food acceptable salts of fatty acids such as stearic, oleic, palmitic, and lauric acids), cationic surfactants (e.g. pharmaceutically, cosmeceutically and / or food acceptable quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride) or any combination thereof. Additional nonlimiting examples of anionic surfactants include but are not limited to: (C6-C8)alkyl- sulfate and / or sulfonate (e.g., sodium or potassium lauryl sulfate, sodium or potassium dodecyl sulfate), fatty alcohol ether sulfate salt (e.g., (C12-C14)alkyl-O-(CH2CH2O)2- SO3-, ZOHARPON ETA 27), polyacrylate (e.g., sodium or potassium polyacrylates), or any combination thereof. Additional non-limiting examples of non-ionic surfactants include but are not limited to: alkyl-polyglycoside (e.g., Triton CG 110, APG 810), polyethyleneglycol-(Cll-C15)alkyl-ether (such as Imbentin AGS / 35), alkoxylated fatty alcohol (such as Plurafac LF221), or any combination thereof. In some embodiments, the nonionic surfactant is or comprises Decyl glucoside. In some embodiments, the cationic surfactant is or comprises guar hydroxypropyl trimonium chloride. In some embodiments, the anionic surfactant is or comprises Disodium Cocoamphodiacetate.

[0108] In some embodiments, the terms “pharmaceutically acceptable carrier” and “cosmetically acceptable carrier are used herein interchangeably.

[0109] In some embodiments, the term “pharmaceutically acceptable carrier” is also referred to as an excipient or adjuvant. As used herein, the term “carrier,” “excipient,” or “adjuvant” refers to any component of a pharmaceutical composition that is not the active agent. As used herein, the term “pharmaceutically acceptable carrier” refers to non-toxic, inert solid, semi-solid liquid filler, diluent, encapsulating material, formulation auxiliary of any type, or simply a sterile aqueous medium, such as saline. Some examples of the materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose, starches such as com starch and potato starch, cellulose andits derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt, gelatin, talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol, polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline, Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible substances used in pharmaceutical formulations. Some non-limiting examples of substances which can serve as a carrier herein include sugar, starch, cellulose and its derivatives, powered tragacanth, malt, gelatin, talc, stearic acid, magnesium stearate, calcium sulfate, vegetable oils, polyols, alginic acid, pyrogen-free water, isotonic saline, phosphate buffer solutions, cocoa butter (suppository base), emulsifier as well as other non-toxic pharmaceutically compatible substances used in other pharmaceutical formulations. Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, excipients, stabilizers, antioxidants, and preservatives may also be present. Any non-toxic, inert, and effective carrier may be used to formulate the compositions contemplated herein. Suitable pharmaceutically acceptable carriers, excipients, and diluents in this regard are well known to those of skill in the art, such as those described in The Merck Index, Thirteenth Edition, Budavari et al., Eds., Merck & Co., Inc., Rahway, N.J. (2001); the CTFA (Cosmetic, Toiletry, and Fragrance Association) International Cosmetic Ingredient Dictionary and Handbook, Tenth Edition (2004); and the “Inactive Ingredient Guide,” U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Office of Management, the contents of all of which are hereby incorporated by reference in their entirety. Examples of pharmaceutically acceptable excipients, carriers, and diluents useful in the present compositions include distilled water, physiological saline, Hartmann solution, Ringer's solution, dextrose solution, Hank's solution, and DMSO. These additional inactive components, as well as effective formulations and administration procedures, are well known in the art and are described in standard textbooks, such as Goodman and Gillman’s: The Pharmacological Bases of Therapeutics, 8th Ed., Gilman et al. Eds. Pergamon Press (1990); Remington’s Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa. (1990); and Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins, Philadelphia, Pa., (2005), each of which is incorporated by reference herein in its entirety.

[0110] The presently described composition may also be contained in artificially created structures such as lipid nanoparticles, liposomes, ISCOMS, slow-releasing particles, and other vehicles which increase the half-life of the peptides or polypeptides in serum. Liposomes for use with the presently described peptides are formed from standard vesicle-forming lipids which generally include neutral and negatively charged phospholipids and a sterol, such as cholesterol. The selection of lipids is generally determined by considerations such as liposome size and stability in the blood. A variety of methods are available for preparing liposomes as reviewed, for example, by Coligan, J. E. et al, Current Protocols in Protein Science, 1999, John Wiley & Sons, Inc., New York, and see also U.S. Pat. Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369.

[0111] In some embodiments, the carrier improves the stability of the active ingredient in a living organism. In some embodiments, the carrier improves the stability of the active ingredient within the pharmaceutical composition. In some embodiments, the carrier enhances the bioavailability of the active ingredient.

[0112] Water may be used as a carrier such as when the active ingredient has a sufficient aqueous solubility, so as to be administered intravenously. Saline solutions, or buffered aqueous solution, as well as aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. In some embodiments, the carrier is a liquid carrier. In some embodiments, the carrier is an aqueous carrier. In some embodiments, the carrier is an aqueous buffer solution (e.g. suitable for injection).

[0113] In some embodiments, the pharmaceutical composition is a liquid at a temperature between 15 to 45°C. In some embodiments, the pharmaceutical composition is a solid at a temperature between 15 to 45°C. In some embodiments, the pharmaceutical composition is a semi-liquid at a temperature between 15 to 45°C. It should be understood that the term “semi-liquid”, is intended to mean materials which are flowable under pressure and / or shear force. In some embodiments, semi-liquid compositions include creams, ointments, gel-like materials, and other similar materials. In some embodiments, the pharmaceutical composition is a semi-liquid composition, characterized by a viscosity in a range from 31,000-800,000 cps.

[0114] Non-limiting examples of carriers for pharmaceutical compositions being in the form of a cream include but are not limited to: non-ionic surfactants (e.g., glyceryl monolinoleate glyceryl monooleate, glyceryl monostearate lanolin alcohols, lecithin mono and di-glycerides poloxamer polyoxyethylene 50 stearate, and sorbitan trioleate stearic acid), anionic surfactants (e.g. pharmaceutically acceptable salts of fatty acids suchas stearic, oleic, palmitic, and lauric acids), cationic surfactants (e.g. pharmaceutically acceptable quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride) or any combination thereof.

[0115] In some embodiments, the pharmaceutical composition being in the form of a cream further comprises a thickener.

[0116] Non-limiting examples of thickeners include, but are not limited to microcrystalline cellulose, a starch, a modified starch, gum tragacanth, gelatin, and a polymeric thickener (e.g. polyvinylpyrrolidone) or any combination thereof.

[0117] In some embodiments, the pharmaceutical composition comprising the quantum dot of the invention is in a unit dosage form. In some embodiments, the pharmaceutical composition is prepared by any of the methods well known in the art of pharmacy. In some embodiments, the unit dosage form is in the form of a tablet, capsule, lozenge, wafer, patch, ampoule, vial, or pre-filled syringe.

[0118] In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the nature of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses can be extrapolated from dose-response curves derived from in-vitro or in-vivo animal model test bioassays or systems. In some embodiments, the effective dose is determined as described hereinabove.

[0119] In another embodiment, the pharmaceutical composition of the invention is administered in any conventional oral, parenteral, or transdermal administration form. In some embodiments, administering is via intravenous, intramuscular, subcutaneous, intratympanic or intradermal administration.

[0120] As used herein, the terms “administering”, “administration”, and like terms refer to any method which, in sound medical practice, delivers a composition containing an active agent to a subject in such a manner as to provide a therapeutic effect. In some embodiments, the pharmaceutical composition is administered via oral (i.e., enteral), rectal, vaginal, topical, sublingual, buccal, nasal, ophthalmic, transdermal, subcutaneous, intramuscular, intraperitoneal, intrathecal, or intravenous routes of administration. The route of administration of the pharmaceutical composition will depend on the disease or condition to be treated. Suitable routes of administration include, but are not limited to, parenteral injections, e.g., intradermal, intravenous, intramuscular, intralesional, subcutaneous, intrathecal, and any other mode of injection as known in the art.

[0121] In some embodiments, the pharmaceutical composition is in a form of, for example, and not by way of limitation, an ointment, cream, gel, injectable solution, paste, foam, aerosol, suppository, pad, or gelled stick.

[0122] In some embodiments, for oral applications, the pharmaceutical composition is in the form of a tablet or a capsule, which can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; or a glidant such as colloidal silicon dioxide. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents. In some embodiments, the tablet of the invention is further film coated. In some embodiments, oral application of the pharmaceutical composition or of the kit is in a form of a drinkable liquid.

[0123] In some embodiments, oral application of the pharmaceutical composition or of the kit is in a form of an edible product.

[0124] For purposes of parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose.

[0125] These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal injection purposes.

[0126] In some embodiments, the carrier may comprise, in total, from about 0.1% to about 99.99% by weight of the pharmaceutical compositions presented herein. In some embodiments, the carrier may comprise in total between 0.1 and 99.99%, between 0.1 and 50%, between 0.2 and 30%, between 0.1 and 70%, between 30 and 99.99%, between 50 and 99.99, by weight of the pharmaceutical compositions presented herein, including any range in between.

[0127] In some embodiments, the carrier is a lipid carrier, configured to form lipid nanoparticles (or micelles in an aqueous solution). In some embodiments, lipid nanoparticles comprises the quantum dot of the invention encapsulated therewithin.

[0128] In some embodiments, the pharmaceutical composition as disclosed herein comprises a therapeutically effective amount of the quantum dots of the invention. Theterm “a therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result in a subject. The exact dosage form and regimen would be determined by the physician according to the patient's condition.

[0129] As used herein, the term "pharmaceutically acceptable salt" refers to any nontoxic salt of the quantum dot of the present invention that, upon administration to a subject, e.g., a human, is capable of providing, either directly or indirectly, a quantum dot of this invention or a therapeutically active metabolite or residue thereof. For example, the term "pharmaceutically acceptable" can mean approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0130] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the quantum dots of this invention include those derived from suitable inorganic and organic acids and bases.

[0131] Non-limiting examples of pharmaceutically acceptable salts include but are not limited to alkali metal salt, earth alkali metal salt, acetate, aspartate, benzenesulfonate, benzoate, bicarbonate, carbonate, halide (such as bromide, chloride, iodide, fluoride), bitartrate, citrate, salicylate, stearate, succinate, sulfate, tartrate, decanoate, edetate, fumarate, gluconate, and lactate or any combination thereof.

[0132] Additional examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.

[0133] Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3- phenylpropionate,T1phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0134] In some embodiments, the quantum dots of the invention are present in the pharmaceutical composition is of pharmaceutical grade purity, i.e., is characterized by a chemical purity of at least about 90%, at least about 95%, greater than 95%, or greater than 99%, and between 90 and 99.999%, between 90 and 95%, between 90 and 97%, between 95 and 99%, including any range in between.

[0135] Compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accommodated by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.System

[0136] In another aspect of the invention, there is provided a system comprising the composition of the invention. In some embodiments, the system comprises the composition (e.g. the pharmaceutical composition or the cosmetic composition) and a suitable light source. In some embodiments, the suitable light source is configured to activate the quantum dots within the composition. In some embodiments, the suitable light source is configured to activate the quantum dots within the composition of the invention upon emission of light having a wavelength overlapping with at least one absorption wavelength (e.g. absorption maximum) of the quantum dots.

[0137] In another aspect of the invention, there is provided a system comprising the composition (e.g. the pharmaceutical composition or the cosmetic composition) of the invention and a suitable light source. In some embodiments, the suitable light source is suitable for activation of the quantum dots. In some embodiments, the suitable light source is configured to emit light at a wavelength suitable for activation of the quantum dots disclosed herein. In some embodiments, the wavelength suitable for activation of thequantum dots is in a near IR range. In some embodiments, the wavelength suitable for activation of the quantum dots is between 780-850nm. In some embodiments, the system comprises the composition and a light source configured to emit light at a wavelength between 780-850nm, between 790 and 820 nm or between 700 and 900 nm. In some embodiments, the system further comprises an application device suitable for administering the composition to the subject.

[0138] In some embodiments, the composition and the light source are within the same compartment or within the same article. In some embodiments, the composition and the light source are in the form of separate articles.

[0139] In some embodiments, the system comprises the quantum dot of the invention and the suitable light source. In some embodiments, the system comprises the composition of the invention and the suitable light source, wherein the system is configured to provide the light source in optical communication with a predetermined target site within the subject. In some embodiments, the predetermined target site is a location within the subject to be treated by the composition of the invention. In some embodiments, the predetermined target site is the administration site. In some embodiments, the composition is in a form of an article within the system, wherein the article is as described below.

[0140] In another aspect of the invention, there is provided a kit comprising the composition (e.g. the pharmaceutical composition or the cosmetic composition) of the invention. In some embodiments, the kit comprises the composition of the invention and the suitable light source, wherein the suitable light source is as described hereinabove. In some embodiments, the composition is in a form of an article within the kit, wherein the article is as described below.

[0141] In some embodiments, the kit contains instructions for preparing the pharmaceutical composition used therein and for how to practice the methods of the invention.

[0142] In some embodiments, the instructions may be recorded on a suitable recording medium or substrate. For example, the instructions may be printed on a substrate, such as paper or plastic, etc.

[0143] In some embodiments, the instructions may be present in the kit as a package insert, in the labeling of the container of the kit or components thereof (i.e., associated with the packaging or sub-packaging) etc. In other embodiments, the instructions are present as an electronic storage data file present on a suitable computerreadable storage medium, e.g. CD-ROM, diskette, etc. In other embodiments, the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g. via the internet, are provided. An example of this embodiment is a kit that includes a web address where the instructions can be viewed and / or from which the instructions can be downloaded.

[0144] In some embodiments, the kit further comprises instructions for administration of the composition to the subject and / or for activation of the quantum dots by providing the suitable light source in optical communication with the predetermined target site within the subject and by irradiating the target site with light at a wavelength suitable for activation of the quantum dots.

[0145] In another aspect of the invention, there is provided an article comprising the composition (e.g. the pharmaceutical composition or the cosmetic composition) of the invention. In some embodiments, the system, kit, or article disclosed herein is characterized by a concentration of the quantum dots of the invention within the composition of between 0.01-200 ug / ml, between 0.001 and 200 ug / ml, between 0.00001 and 200 ug / ml, including any range between.

[0146] In some embodiments, the article disclosed herein is a medical article. In some embodiments, the article disclosed herein is a cosmetic article. In some embodiments, the quantum dots within the article are in a form of a solid composition or in a form of a liquid or semi-liquid composition.

[0147] In some embodiments, the article is in a form of a solid, or in a form of an injectable composition, gel, ointment, wound dressing or patch. In some embodiments, the article is a phototherapeutic article.

[0148] In some embodiments, the phototherapeutic article is activated by light irradiation at a wavelength between 780 and 850nm, between 800 and 850nm, between 790 and 830nm, between 780 and 830nm, between 780 and 820nm, between 780 and 810nm, between 800 and 830nm, between 800 and 820nm, including any range between. In some embodiments, the phototherapeutic article is configured to be activated upon administration thereof to a subject.

[0149] In some embodiments, the light irradiation (in conjunction with the system / kit / article of the invention) is performed in a non-invasive manner, via external activation, i.e. the suitable light source is position outside of the subject’s organism.

[0150] In some embodiments, the light source is selected from a lamp (e.g. a broad spectrum VIS, NIR or UV-VIS lamp), a light emitting diode, LASER, etc.

[0151] In an exemplary embodiment, after administration, the quantum dots within the composition are externally activated by near-infrared (NIR) light (e.g. 800-850nm) from a light-emitting diode (LED) or laser.

[0152] For treating SSNHL, the composition of the invention can be injected intratympanic or in another technique. Then, the photocatalytic nanoparticle activation will be external, through the ear drum. NIR light can penetrate the ear drum hence eliminating the need for multiple injections.

[0153] For organ transplantation, the composition can be delivered to the host in the translation process, before closing the patients. Additional light activation can be performed externally during the acceptance and recovery process. This can also be performed on engineered tissue transplants.

[0154] In some embodiments, the system, the article, or the kit of the invention is for use in the treatment or prevention of a disease or a disorder, in a subject in need thereof. In some embodiments, the system, the article, or the kit of the invention is for use in the treatment of a disease / disorder or a condition associated with cell damage. In some embodiments, the system, the article, or the kit of the invention is for use in induction or enhancement of cell proliferation and / or cell regeneration in a subject in need thereof.

[0155] In some embodiments, the system, the article, or the kit of the invention is for use in induction or enhancement of proliferation and / or regeneration of a neuronal cell. In some embodiments, the system, the article, or the kit of the invention is for use in the treatment of neuronal cell damage, and / or a disease or condition associated therewith.

[0156] In some embodiments, the system, the article, or the kit of the invention is for use in induction or enhancement of wound healing (e.g. healing of a tissue damage, such as skin bum, skin wound, or a tissue damage associated with organ transplantation).

[0157] In some embodiments, the system, the article, or the kit of the invention is for use in the treatment or prevention of a neurodegenerative disease. In one embodiment, the neurodegenerative disorder is selected from the group comprising: Alzheimer ’s disease, multiple sclerosis, dementia, Parkinson’s disease, Huntington’s disease, Down syndrome, Amyotrophic lateral sclerosis (ALS), and prion disease or any combination thereof.

[0158] In some embodiments, the composition, the system, the article, or the kit of the invention is for use in the treatment or prevention of a disease, disorder or condition associated with neuronal damage, cell transplantation, skin tissue damage, or any combination thereof. In some embodiments, the disease is sudden sensorineural hearing loss (SSNHL).

[0159] In some embodiments, the composition, the system, the article, or the kit of the invention is for use in the treatment or prevention of SSNHL. In some embodiments, the composition, the system, the article, or the kit of the invention is for use in the treatment or prevention of a disease, disorder or condition associated with neuronal damage.Definitions

[0160] As used herein, the term "alkyl" describes an aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 21 to 100 carbon atoms, and more preferably 21-50 carbon atoms. Whenever a numerical range e.g., “21- 100”, is stated herein, it implies that the group, in this case the alkyl group, may contain 21 carbon atom, 22 carbon atoms, 23 carbon atoms, etc., up to and including 100 carbon atoms. In the context of the present invention, a "long alkyl" is an alkyl having at least 20 carbon atoms in its main chain (the longest path of continuous covalently attached atoms). A short alkyl therefore has 20 or less main-chain carbons. The alkyl can be substituted or unsubstituted, as defined herein.

[0161] The term "alkyl", as used herein, also encompasses saturated or unsaturated hydrocarbon, hence this term further encompasses alkenyl and alkynyl.

[0162] The term "alkenyl" describes an unsaturated alkyl, as defined herein, having at least two carbon atoms and at least one carbon-carbon double bond. The alkenyl may be substituted or unsubstituted by one or more substituents, as described hereinabove.

[0163] The term "alkynyl", as defined herein, is an unsaturated alkyl having at least two carbon atoms and at least one carbon-carbon triple bond. The alkynyl may be substituted or unsubstituted by one or more substituents, as described hereinabove.

[0164] The term "cycloalkyl" describes an all-carbon monocyclic or fused ring (i.e. rings which share an adjacent pair of carbon atoms) group where one or more of the rings does not have a completely conjugated pi-electron system. The cycloalkyl group may be substituted or unsubstituted, as indicated herein.

[0165] The term "aryl" describes an all-carbon monocyclic or fused-ring polycyclic (i.e. rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. The aryl group may be substituted or unsubstituted, as indicated herein.

[0166] The term "alkoxy" describes both an O-alkyl and an -O-cycloalkyl group, as defined herein.

[0167] The term "aryloxy" describes an -O-aryl, as defined herein.

[0168] Each of the alkyl, cycloalkyl and aryl groups in the general formulas herein may be substituted by one or more substituents, whereby each substituent group can independently be, for example, halide, alkyl, alkoxy, cycloalkyl, nitro, amino, hydroxyl, thiol, thioalkoxy, carboxy, amide, aryl and aryloxy, depending on the substituted group and its position in the molecule. Additional substituents are also contemplated.

[0169] The term "halide", "halogen" or “halo” describes fluorine, chlorine, bromine, or iodine.

[0170] The term “haloalkyl” describes an alkyl group as defined herein, further substituted by one or more halide(s).

[0171] The term “haloalkoxy” describes an alkoxy group as defined herein, further substituted by one or more halide(s).

[0172] The term “hydroxyl” or "hydroxy" describes a -OH group.

[0173] The term "mercapto" or “thiol” describes a -SH group.

[0174] The term "thioalkoxy" describes both an -S-alkyl group, and a -S-cycloalkyl group, as defined herein.

[0175] The term "thioaryloxy" describes both an -S-aryl and a -S-heteroaryl group, as defined herein.

[0176] The term “amino” describes a -NR’R” group, with R’ and R” as described herein.

[0177] The term "heterocyclyl" describes a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen, and sulfur. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. Representative examples are piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholino and the like.

[0178] The term "carboxy" or "carboxylate" describes a -C(O)OR' group, where R' is hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl (bonded through a ring carbon) or heterocyclyl (bonded through a ring carbon) as defined herein.

[0179] The term “carbonyl” describes a -C(O)R' group, where R' is as defined hereinabove.

[0180] The above-terms also encompass thio-derivatives thereof (thiocarboxy and thiocarbonyl).

[0181] The term “thiocarbonyl” describes a -C(S)R' group, where R' is as defined hereinabove.

[0182] A "thiocarboxy" group describes a -C(S)OR' group, where R' is as defined herein.

[0183] A "sulfinyl" group describes an -S(O)R' group, where R' is as defined herein.

[0184] A "sulfonyl" or “sulfonate” group describes an -S(O)2R' group, where R' is as defined herein.

[0185] A "carbamyl" or “carbamate” group describes an -OC(O)NR'R" group, where R' is as defined herein and R" is as defined for R'.

[0186] A "nitro" group refers to a -NO2 group.

[0187] The term "amide" as used herein encompasses C-amide and N-amide.

[0188] The term "C-amide" describes a -C(O)NR'R" end group or a -C(O)NR'-linking group, as these phrases are defined hereinabove, where R' and R" are as defined herein.

[0189] The term "N-amide" describes a -NR"C(O)R' end group or a -NR'C(O)- linking group, as these phrases are defined hereinabove, where R' and R" are as defined herein.

[0190] The term "carboxylic acid derivative" as used herein encompasses carboxy, amide, carbonyl, anhydride, carbonate ester, and carbamate.

[0191] A "cyano" or "nitrile" group refers to a -CN group.

[0192] The term "azo" or "diazo" describes an -N=NR' end group or an -N=N- linking group, as these phrases are defined hereinabove, with R' as defined hereinabove.

[0193] The term "guanidine" describes a -R'NC(N)NR"R"' end group or a -R'NC(N) NR"- linking group, as these phrases are defined hereinabove, where R', R" and R'" are as defined herein.

[0194] As used herein, the term “azide” refers to a -N3 group.

[0195] The term “sulfonamide” refers to a -S(O)2NR'R" group, with R' and R" as defined herein.

[0196] The term “phosphonyl” or “phosphonate” describes an -OP(O)-(OR')2 group, with R' as defined hereinabove.

[0197] The term “phosphinyl” describes a -PR'R" group, with R' and R" as defined hereinabove.

[0198] The term “alkylaryl” describes an alkyl, as defined herein, which is substituted by an aryl, as described herein. An exemplary alkylaryl is benzyl.

[0199] The term "heteroaryl" describes a monocyclic (e.g. C5-C6 heteroaryl ring) or fused ring (i.e. rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen, and sulfur and, in addition, having a completely conjugated pi-electron system. In some embodiments, the terms“heteroaryl” and “C5-C6 heteroaryl” are used herein interchangeably. Examples, without limitation, of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine. The heteroaryl group may be substituted or unsubstituted by one or more substituents, as described hereinabove. Representative examples are thiadiazol, pyridine, pyrrole, oxazole, indole, purine, and the like.

[0200] As used herein, the terms "halo" and "halide", which are referred to herein interchangeably, describe an atom of a halogen, that is fluorine, chlorine, bromine, or iodine, also referred to herein as fluoride, chloride, bromide, and iodide.

[0201] The term “haloalkyl” describes an alkyl group as defined above, further substituted by one or more halide(s).

[0202] As used herein the term “about” refers to ± 10 %.

[0203] The terms "comprises", "comprising", "includes", "including", “having” and their conjugates mean "including but not limited to". The term “consisting of’ means “including and limited to”. The term "consisting essentially of' means that the composition, method or structure may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure. In some embodiments, “consists essentially of’ encompasses between 80 and 100%, between 80 and 99%, between 90 and 99%, between 90 and 100%, between 92 and 99%, between 93 and 99%, between 95 and 99%, between 95 and 97% between 93 and 100%, between 95 and 100%, between 97 and 99%, between 97 and 100% by weight of the composition consists of the listed constituents and is devoid of additional ingredients which contribute to the essential properties of the composition, as disclosed herein.

[0204] The word “exemplary” is used herein to mean “serving as an example, instance or illustration”. Any embodiment described as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments and / or to exclude the incorporation of features from other embodiments.

[0205] The word “optionally” is used herein to mean “is provided in some embodiments and not provided in other embodiments”. Any particular embodiment of the invention may include a plurality of “optional” features unless such features conflict.

[0206] As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0207] As used herein, the term “substantially” refers to at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, including any range or value therebetween.

[0208] Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0209] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging / ranges between” a first indicate number and a second indicate number and “ranging / ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

[0210] As used herein, the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

[0211] As used herein, the term “treating” includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.

[0212] As used herein, the term “prevention” of a disease, disorder, or condition encompasses the delay, prevention, suppression, or inhibition of the onset of a disease, disorder, or condition. As used in accordance with the presently described subject matter,the term "prevention" relates to a process of prophylaxis in which a subject is exposed to the presently described active ingredients prior to the induction or onset of the disease / disorder process. This could be done where an individual has a genetic pedigree indicating a predisposition toward occurrence of the disease / disorder to be prevented. For example, this might be true of an individual whose ancestors show a predisposition toward certain types of inflammatory disorders.

[0213] In those instances where a convention analogous to "at least one of A, B, and C, etc." is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., "a system having at least one of A, B, and C" would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase "A or B" will be understood to include the possibilities of "A" or "B" or "A and B."

[0214] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0215] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.EXAMPLES

[0216] Present invention in some embodiments thereof includes the use of a photocatalytic nanoparticles-based approach for tissue regeneration. Photocatalytic nanoparticles of the invention are not toxic at a therapeutic concentration and allowphotoactivation by NIR light with high tissue penetration depth, being suitable for inbody activation by external light stimulation.Here, the inventors synthesized and optimized Ag2S quantum dots (QDs) as a water stable and soluble, and heavy metal-free, photocatalytic QDs, which are expected to be biocompatible, based on the experimental results provided herein. In addition, Ag2S QDs are activated by NIR light which allows external activation and spatiotemporal control in body electron generation. To enhance the QDs photocatalytic activity, Ni doping was added.QD synthesis

[0217] The inventors synthesized the QDs by using a synthesis route with silver nitrate (AgNCh) and 3 -Mercaptopropionic acid (3 -MPA) (or alternatively with Thioglycolic acid (TGA)) as reagents in ethylene glycol (EG). The reaction was carried out under a nitrogen-inert environment. First, EG was injected into the system and bubbled with nitrogen at 25°C with vigorous stirring. Next AgNOs and 3-MPA dissolved in EG were injected separately into the system to reach 5,10 mM final concentration accordingly. In the case of doping QDs synthesis NitNOsE was added at the expense of AgNOs. The system was heated to 110°C for 45 min and then incubated at 145 °C for about 60 min, to result in QDs with an average particle size of about 7nm, determined based on TEM (STEM) image.

[0218] The resulting solution was cooled down at room temperature and then diluted with acetone in a 3:7 reaction: acetone ratios and was left overnight to let the QDs to crushed out. The product was then washed and purified 3 times with acetone then redissolved in double distilled water lOmM NaOH solution to obtain water soluble Ag2S QDs decorated with carboxyl group ligands.QD characterization

[0219] Physical characterization of the QDs showed that the mean particle size was about 7 nm + / -2 nm. Further, the QDs were characterized by STEM Energy-dispersive X-ray (EDX) (Figure 6B-6E).EXAMPLE 1Optical properties and photocatalytic activity

[0220] In photocatalytic nanoparticles, a photon excites an electron from the valance band (VB) to the conduction band (CB) and generates charge separation and electronhole pair (Fig 7. A). The energy gap between the VB and the CB is called the band gapand is unique to each photoelectric material. The band gap in the QDs synthesized here was estimated to be 1.3 eV, calculated from the measured absorbance spectra and Tauc Plot.

[0221] The UV-VIS absorbance spectra, emission spectra with 380nm excitation, and excitation spectra with 850nm emission were measured (Fig. 4A) using a TECAN plate reader. Two absorbance peaks were observed at 380 and 800nm, as well as two excitation peaks were at 800, and 370 nm. An emission peak was observed at 850nm.

[0222] Transmission electron microscopy (TEM) images showed spherical nanoparticles with about 7±2nm diameter (Fig. 4B) and an average particle size of about 7nm (Fig. 4C).

[0223] To measure photocatalytic activity, 200pg / ml QDs were added to 20mg / lit MB solution in phosphate buffer saline (PBS), mimicking the salt concentration in biological environments. All solutions were kept in the dark for 30 min to ensure equilibrium, then illuminated continuously with 8 lOnm LED light in 39mw per 2.5ml sample while stirring vigorously. Aliquots were collected every 30 minutes. Aliquots from the reactions were taken in 30 min intervals. The samples were centrifuged for 10 minutes at 10,000g then their absorbance in 664nm was measured, to calculate the part of MB that was decomposed. In the mentioned MB photocatalysis assay, samples containing Ag2S QDs with and without 3%wt Ni doping were illuminated with 810nm LED light for 90 min. The Ni doped QDs showed an increase in photocatalysis activity, decomposed 44+7% of the MB after 90min, compared with 28+8% at the un doped samples (Fig.5A). This is a 57% increase in the MB decomposition and photocatalytic activity, demonstrating improved performance.

[0224] Samples with Ag2S 3%wt Ni illuminated were also illuminated with 400nm UV light decomposed 30% of the MB (Fig.5B). From this we can conclude that 810nm NIR illumination demonstrates improved photocatalytic activity and 46% activity increase compared with 400nm illumination.

[0225] The control samples in the both experiment include samples with QDs with and without Ni doping left in the dark, and samples without QDs in the dark and under 400 and 810nm illumination. All the control samples show negligible MB decomposition. This ensures the MB decomposition resulted from the light interacting with the QDs.Photoelectric Activity of Ag S QDs with TGA versus QDs with 3-MPA

[0226] Additional experiment was performed as described above comparing the photocatalytic activity of QD decorated with different ligands (TGA and MPA).Surprisingly, QDs decorated with TGA ligands didn’t show any significant photoelectric activity. In sharp contrast, QDs decorated with 3-MPA resulting show a significant decrease in the MB concentration with illumination time, compared to the controls of QDs in the dark and negative controls (N.C) without QDs, exposed to light or in the dark. This indicates a photocatalytic activity and proves the QDs emit electrons when illuminated with 810nm light (Fig. 5C).Optimization of the average particle size of the QDs

[0227] QDs formation is accomplished during the incubation stage at 145°C (see QD synthesis section, above). The inventors observed that it is possible to control the average particle size of the QDs by varying the incubation time. As the incubation time increases, the QD size increases. Accordingly, the inventors synthesized QDs having a different average particle size by varying the incubation time period.

[0228] First, the inventors synthesized QDs decorated with MPA ligands, having an average size of about 3-5nm by performing the synthesis as disclosed above and by keeping the incubation time in the range between 15-45 min. The spectral properties and photocatalytic activity of the QDs were examined. Surprisingly, these QDs did not show a strong fluorescent emission and did not demonstrate any photocatalytic activity, as evaluated using methylene blue assay under 380nm and 810nm light.

[0229] Furthermore, the inventors synthesized similar QDs with an average size of greater than 10 nm (about ll-20nm) by performing the synthesis procedure as disclosed above and by keeping the incubation time in the range between 75 -120 min. The spectral properties and photocatalytic activity of the QDs were examined.

[0230] Although, these QDs exhibited a strong fluorescent emission, they were not soluble / dispersible in an aqueous solution containing salts. QDs precipitated upon mixing thereof with an aqueous solvent (an aqueous salt solutions such as PBS or cell culture medium) at a concentration ranging between about 1-200 pg / ml. Hence, the inventors postulated that QDs with an average size of above lOnm are not water dispersible and thus are not suitable for in-vivo administration (e.g. for inducing tissue regeneration).

[0231] To conclude, the Ag2S 3% Ni QDs with MPA ligands and having an average particle size of about 7-8nm (based on TEM image evaluation) were the most promising candidates to photoelectric stimulate neurons. Hence, those QDs were used in further in- vitro experiments.EXAMPLE 2Viability / Toxicity experiments

[0232] To ensure biocompatibility of the synthesis QDs, we performed presto blue viability assays with Human Embryonic Kidney (HEK)293 cells, exposed to Ag2S 3%wt Ni in the dark for 24 hours, DRG cells for 24hr (fig 8c) and SHSY-5Y for 1 week (Fig 8a). No toxic effect was observed in all the tested concentrations (400-0.39 pg / ml) (Fig. la). To test the QD's ability to enhance proliferation, we used two different cell types. Ag2S 3% Ni (200-0.78 pg / ml) was added to confluent seeded SHSY-5Y neuroblastoma cells and HEK cells seed uniformly in 96 plate wells in 2 groups; light and dark. Ag2S 3%QDs were added to the cells in various concentrations (200-0.39 pg / ml). Next, the light group was illuminated with 810n FED light for 30sec, one LED for a well, then kept in the dark. The dark group was kept in the dark since the QDs were added. To measure the cell growth, cell viability was measured with presto blue assay 20 hours after illumination with presto blue viability assay. In both cell types, cells with the QDs exposed to light showed increased viability of up to 170% in the HEK and 130% in SHSY-5Y compared to cells that were kept in the dark (Figs. 8B and 1C).

[0233] An additional similar experiment with HEK cells was conducted in which the cells were imaged to observe their proliferation. Cells were seeded uniformly in 24 wells plate, with and without lOpg / ml Ag2S 3% Ni and were imaged 20 hours after 30 sec 810nm light illumination. The nuclei were stained with hoechst, and the cells’ cytoplasm was stained with calcian. The images showed a clear increment in cell proliferation in the samples treated with QDs and illuminated, compared to samples kept in the dark and samples without QDs (Fig. IB). The described result demonstrates the ability of NIR activating photocatalytic Ag2S 3% Ni QDs to enhance cell proliferation and the potential in tissue regeneration.

[0234] The Ag2S 3% Ni QDs toxicity was tested in-vitro by measuring viability of human cell lines. The viability was tested on both neuronal cell line from a human source (SHSY-5Y), and dorsal root ganglions (DRG) primary neurons from rats. All viability measurements were performed with presto blue viability assay.

[0235] The viability is SHSY-5Y neurons was measured after 7 days incubation in the dark with various QDs concentration (Fig. 8A). No toxic affect was observed at concentrations up to lOpg / ml (this concentration was further used to induce exonal growth).

[0236] To examine NIR light and QDs activation on the cell toxicity, SHSY-5Y neurons with lOpg / ml were illuminated continuously for 0.5-5min using an 8 lOnm LEDs and 0.2mw / cm2. Next, the cells were incubated in the dark for 24 and their viability was measured (Fig. 8B). An increase in cell viability was observed in all the QDs illuminated samples, compared to the samples without the QDs. This surprising findings demonstrate that the QDs are nontoxic and even enhance cell proliferation.

[0237] Further, DRG primary neurons viability was tested, after 24hr incubation with or without lOpg / ml QDs, in the dark or followed by 2hr of 810nm LEDs, 0.2mw / cm2 illumination, in Isec on 4sec off Cycles. No toxicity was observed in this experiment (Figure 8C). To this end, the inventors have concluded that the tested QDs are safe to use for medical applications to a human subject, such as for neuronal regeneration.EXAMPLE 3Neuronal Regeneration

[0238] Neurons communicate with firing through neuronal networks. In nerve injuries, these networks are damaged, preventing motor and sensory signals from being transmitted, hence preventing basic functions. To restore nerve function, recover the damaged nerve, and recreation of a new neuronal network is required. This is achieved by the axonal growth of existing neurons. Thus, axonal growth is required for nerve regeneration.

[0239] The inventors demonstrate the use of QDs as a minimally invasive approach, to optoelectrical stimulate neurons and induce exonal growth. The QDs can be injected into the patients, illuminated externally, and induce neuronal recovery.

[0240] SHSY-5Y neuronal cell line was used in a model, to explore the QDs' ability to induce axonal growth. To each sample, of 16.5mm diameter well seeded with l*105cells, we added 500 ul of lOpg / ml QDs in cell media. The cells were exposed to 810nm, 0.1 mw / mm2LED light in 1 sec on, 4 sec off cycles. The illumination duration was 30 min, 60 min, or no light daily, for 5 continuous days, followed by 2 days of incubation in the dark. After 4 days, the media was replaced with fresh media. On day 8, the cells were analyzed through flow cytometry or immunofluorescence imaging. For imaging, the cells were stained with Hoechst nuclei stain and anti [33 tubulin antibodies (Fig. 9A). [33 tubulin is a protein expressed in neurons' cytoplasm and axons. [33 tubulin expression increases with axonal growth at SHSY-5Y. The images were analyzed by IMARIS software,analyzing the axon length (Fig. 9C) and branch level (Fig. 9B), of over 500 neurons per sample. The image analysis showed an increase in the average axon length with the use of QDs and NIR light illumination. The greater length increase was observed in the samples with QDs and 60min daily illumination. The axons in this sample were 6 times longer than the untreated samples' average length. Additionally, neuronal branching increased by 10 fold in the 60min, QDs samples compared to the untreated control. Both of those parameters indicate the creation of a neuronal network.

[0241] The QDs effect on neuronal protein production was tested using flow cytometry (Fig. 9D). In this experiment the cells were stained with anti Tyrosine Hydroxylase (TH) and anti Q3 tubulin (QT) antibodies. Both TH and PT are associated with axonal growth and are produced as part of the axonal growth mechanism. Flow Cytometry quantification analysis showed an increase in the production of TH by 1.5 fold and PT by 2 fold in the samples treated with QDs compared to the untreated samples. From these results, we conclude that the QDs provide the necessary electrical neuronal stimulation to induce nerve regeneration. This breakthrough enables utilizing Ag2S 3% Ni QDs properties for precise and controlled optoelectrical stimulation nanomedicine, and minimally invasive nerve therapy.

[0242] The inventors postulate that the QDs of the invention can be applied as means (medical / cosmetic articles) for light triggered tissue regeneration. Specifically, medical / cosmetic articles comprising the QDs of the invention can be used for a controlled treatment (e.g. spatiotemporal controlled treatment) for enhancing cell proliferation and for treatment of diseases / conditions related thereto (e.g. for tissue regeneration, treatment of tissue damage, such as neuronal damage and related diseases) in a subject.

[0243] Specifically, the inventors presume usage of the QD disclosed herein in regenerative medicine, due to its potential to facilitate the restoration of damaged tissues. Additional applications include but are not limited to: restoration of damage to the peripheral nerve system in cases such as SNHL; as a cosmetic product- to regenerate skin tissue and skin tightening for a young look; Spinal cord and traumatic nerve damage; for wound healing, tissue recovery after radiation damage, skin trauma and burns in a stimuli responsive and minimally invasive approach. QD of the invention can be applied as the only treatment or in combination with additional treatments like HBOT, to reduce the treatment period and improve the therapeutic effect and results.

[0244] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims

CLAIMSWhat is claimed is:

1. A composition comprising Ag2S quantum dots, each of the Ag2S quantum dots (QD) is bound to a plurality of ligands represented by Formula 1, including any salt thereof:, wherein: n is an integer, ranging between 2 and 5;X is O, S or NH;R1 is H, or represents one or more substituents selected from -OH, halogen, oxo, carbonyl, OR’, -NO2, -CN, -C0NH2, -CONR’2, -CNNR’2, -CSNR’2, -CONH- OH, -C0NH-NH2, -NHCOR’, -NHCSR’, -NHCNR, -NC(=O)OR’, - NC(=O)NR’, -NC(=S)OR’, -NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, - SO2N(R’)2, -NHNR’2, -NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl-C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl-NR’2, C1-C6 alkyl-SR’, -CONH(C1- C6 alkyl), -CON(C1-C6 alkyl)2, -C02H, -C02R’, -OCOR, -OCOR’, - OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclic alkyl, or a combination thereof as allowed by valency;R is H, or represents one or more substituents selected from Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, halo, -NO2, -CN, -OR’, -NH2, carbonyl, -CONH2, -CONR’2, -CNNR2, -CSNR2, -CONH-OH, -CONH- NH2, -NHCOR’, -NHCSR’, -NHCNR’, -NC(=O)OR’, -NC(=O)NR’, - NC(=S)OR’, -NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, - NHNR’2, -NNR’, -NH(C1-C6alkyl), -N(CI-C6alkyl)2, hydroxy(Ci-C6alkyl), hydroxy(Ci-C6 alkoxy), alkoxy(Ci-C6 alkyl), alkoxy(Ci-C6 alkoxy), amino(Ci-C6 alkyl), -CONH(CI-C6alkyl), -CON(CI-C6alkyl)2, -CO2H, -CO2R’, -OCOR’, -OCOR’, -OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, a heteroatom, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, or a combination thereof, wherein each R’ is independently selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl a heteroatom, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, or any combination thereof, as allowed by valency; and said QD are characterized by an average particle size below lOnm.

2. The composition of claim 1, wherein said QD further comprise up to 5% of a dopant metal by weight of said QD.

3. The composition of claim 2, wherein said dopant metal is selected from the group consisting of Nickel (Ni), Copper (Cu), Iron (Fe), Zinc (Zn), Manganese (Mn), Cobalt (Co), Silver (Ag), Gold (Au), Cadmium (Cd), Lead (Pb), and Platinum (Pt), including any combination thereof.

4. The composition of claim 2, wherein said QD are characterized by a negative zeta potential; and wherein said QD are characterized by an average particle size of between about 8 and about lOnm.

5. The composition of any one of claims 1 to 4, wherein said QD are water soluble or water dispersible up to a concentration of lOmg / ml.

6. The composition of claim 5, wherein QD are water soluble or water dispersible up to a concentration of 500 ug / ml; and wherein said water soluble or water dispersible comprises solubility or dispersibility of said QD in an aqueous salt solution.

7. The composition of any one of claims 1 to 6, wherein said plurality of ligands are covalently attached to a surface of said QD; and wherein said QD are characterized by an average particle size of between 5 and 9nm.

8. The composition of any one of claims 1 to 7, wherein said QD are characterized by an average particle size of about 7nm, as determined by TEM image analysis.

9. The composition of any one of claims 1 to 8, wherein said plurality of ligands are:, including any salt thereof.

10. The composition of any one of claims 1 to 9, wherein said QD are characterized by an absorption maximum at (i) a first wavelength range between about 380 and about 400 nm; at (ii) a second wavelength range between about 790 and about 820, or both (i) and (ii) and by an emission maximum at a wavelength range between about 840 and about 870nm.

11. The composition of any one of claims 1 to 10, wherein the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

12. The composition of claim 11, wherein a concentration of said QD within the pharmaceutical composition is between 0.01 and 200 ug / ml.

13. The composition of claim 11 or 12, wherein said pharmaceutical composition is for use in at least one of: (i) enhancement and / or induction of cell proliferation; (ii) enhancement and / or induction of cell regeneration; (iii) promoting engraftment of a transplanted tissue.

14. The composition of claim 13, wherein said cell comprises a neuronal cell, an endothelial cell, an epithelial cell, a muscle cell, and a fibroblast, including any combination thereof.

15. The composition of claim 14, wherein said cell is the neuronal cell and wherein said cell regeneration comprises increasing axonal length and / or neuronal branching.

16. The composition of claim 15, wherein said neuronal cell is a degenerated neuronal cell comprising at least one degenerated axon; and wherein increasing is by at least 10%, compared to an untreated degenerated neuronal cell.

17. A method for treating a disease or a disorder in a subject, comprising administering to the subject a therapeutically effective amount of composition of any one of claims 1 to 12, thereby treating said disease; wherein said method further comprises excitation of said QD at a suitable wavelength.

18. The method of claim 17, wherein said administering is by systemic administration.

19. The method of claim 17, wherein said administering comprises intravenous, intramuscular, subcutaneous, intratympanic or intradermal administration.

20. The method of any one of claims 17 to 19, wherein said disease or said disorder is associated with neuronal damage, neuronal cell degeneration, abnormal cell growth, axon degeneration, cell transplantation, skin tissue damage, or any combination thereof.

21. The method of claim 20, wherein said disease or said disorder is selected from Sudden sensorineural hearing loss (SSNHL), a neurodegenerative disease, a central nervous system (CNS) disease, a traumatic nerve damage, a peripheral nervous system (PNS) disorder and an ocular disorder, including any combination thereof.

22. The method of any one of claims 17 to 21, wherein said excitation comprises light irradiation of said subject; and wherein said suitable wavelength is between about 790 and about 830nm.

23. The method of claim 22, wherein said light irradiation is performed for a time period between 1 and 200 minutes.

24. The method of claim 22 or 23, wherein said light irradiation comprises a light radiation dose ranging between 0.05 and 5mw / cm2.

25. A cosmetic composition comprising the composition of any one of claims 1 to 10 and a cosmetically acceptable carrier.

26. An article comprising the pharmaceutical composition of any one of claims 11-12 or the cosmetic composition of claim 24, and further comprising instructions for activating the QD via light irradiation at a wavelength ranging between 380 and 420nm or between 790 and 830nm.

27. The article of claim 26, wherein said article is in a form of: injectable composition, gel, ointment, wound dressing or patch.

28. The article of claim 26 or 27, being a medical kit or a cometic article.

29. The article of claim 28, wherein said medical kit is for use in the treatment of a disease or a disorder in a subject.

0. The article of claim 29, wherein said disease or said disorder is associated with neuronal damage, neuronal cell degeneration, abnormal cell growth, axon degeneration, cell transplantation, skin tissue damage, or any combination thereof.

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