NL2018923B1

NL2018923B1 - Cerenkov Chemotherapy and kit of parts

Info

Publication number: NL2018923B1
Application number: NL2018923A
Authority: NL
Inventors: Georgieva Denkova Antonia; Eelkema Rienk; Cornelis Laan Adrianus; Weller Andreas
Original assignee: Univ Delft Tech
Priority date: 2017-05-16
Filing date: 2017-05-16
Publication date: 2018-11-23
Also published as: WO2018212649A1

Abstract

The present invention is in the field of a kit of parts comprising a radionuclide and a therapeutic compound, a medic— ament comprising said kit of parts, and a method of treating a disease by administering said kit of parts, in particular for treating a cancer or a metastase, wherein the therapeutic com— pound is released or activated.

Description

Title Cerenkov Chemotherapy and kit of parts

FIELD OF THE INVENTION

The present invention is in the field of a kit of parts comprising a radionuclide and a therapeutic compound, a medicament comprising said kit of parts, and a method of treating a disease by administering said kit of parts, in particular for treating a cancer or a métastasé, wherein the therapeutic compound is released or activated.

BACKGROUND OF THE INVENTION A radionuclide is an atom with an unstable nucleus, which is a nucleus characterized by excess energy available to be imparted either to a newly created radiation particle within the nucleus or to an atomic electron. The radionuclide, in this process, undergoes radioactive decay, and emits one or more of the following; photons, negatron, positron, or alpha particles, directly or indirectly. These particles constitute ionizing radiation. Radionuclides occur naturally, and can also be artificially produced.

Radionuclides are often referred to by chemists and physicists as radioactive isotopes or radioisotopes. Radioisotopes with suitable half-lives play an important part in a number of constructive technologies (for example, nuclear medicine).

Radionuclides are used in two major ways: for their chemical properties and as sources of radiation. Radionuclides of familiar elements such as carbon can serve as tracers because they are assumed to be chemically identical to the nonradioactive nuclides, so almost all chemical, biological, and ecological processes treat them in the same way.

Radioisotopes per se are also a method of treatment in hemopoietic forms of tumors; the success for treatment of solid tumors has been limited. More powerful gamma sources sterilize syringes and other medical equipment.

Cerenkov luminescence may be emitted when a charged particle traverses a dielectric medium with a velocity greater than the phase velocity of light in the medium. The Cerenkov luminescence typically originates from ß-radioisotopes. The light is then emitted on a cone around the particle direction, with a typical continuous spectrum. In tissue emitted light may be highly scattered and absorbed before reaching a surface, and the tissue's optical properties tend to favor the transmission of the red-infrared light, where Cerenkov emission is minimal.

Globally more than 8 million people may die from cancer every year. A majority thereof results from metastasized cancer cells, which are found extremely difficult to attack. At present metastasized cancer is treated primarily by chemotherapy. Since this therapy is systemic and tumor targeting is still far from optimal, chemotherapy may cause severe damage to (surrounding) healthy tissue, leading to rather adverse health effects including tissue damage, preliminary termination of therapy programs and severe decrease in quality of life for the patient. One way to reduce side effects caused by undesired damage to healthy tissue is to design drug molecules or drug carriers that release the drug only at the tumor site, due to an internal or external trigger. Photodynamic therapy (PDT, light-induced activation of drugs using a sensitizer molecule) is one such example that has proven to be very effective with limited adverse health effects. However, this therapy is limited to tumors of known location and, due to short penetration depth of light in tissue, to superficial tumors. Similarly, other external triggers can only treat localized solid tumors, while internal triggers rely on tumor dependent factors to release the drug, which often fail due to tumor microenvironment diversity.

Targeted therapy is a medical treatment typically used for cancer. Targeted therapy may be aimed at blocking growth of cancer cells or even destroy said cells. The term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy, which distinguishes therewith from chemotherapy. The two can be combined.

Another form of targeted therapy may involve use of nanoengineered enzymes to bind to a tumor cell thereby effectively eliminating it from the body. Targeted cancer therapies are considered more effective and less harmful to normal cells. Many targeted therapies may be considered as examples of immunotherapy developed by the field of cancer immunology.

Targeted therapies may relate to chemical entities that target or even preferentially target a protein or enzyme, such as one that carries a mutation or other genetic alteration that is specific to cancer cells and is hence not found in other host tissue. An example is a kinase inhibitor with exceptional affinity for the oncofusion protein BCR-Abl.

There are targeted therapies for colorectal cancer, head and neck cancer, breast cancer, multiple myeloma, lymphoma, prostate cancer, melanoma and other cancers.

For drug delivery typically a vehicle or carrier is used. A carrier may relate to a liquid, such as water and oils, a diluent, typically water-based, such as a saline solution.

Photo-electrochemical processes may involve transforming light into other forms of energy. An example thereof is photosensitization, which relates to transferring energy of absorbed light. After absorption the energy may be transferred to certain reactants. In particular this process may be used when chemical reactions require light certain wavelengths that are not readily available. In an example mercury (Hg) absorbs radiation at 184.9 and 253.7 nm. It is a commonly used sensitizer. So when for instance mercury vapor is mixed with a chemical compound as ethylene, and the compound is irradiated therewith, a photodecomposition of ethylene to acetylene occurs by transfer of energy to the ethylene molecules. Cadmium, noble gases, zinc, benzophenone, and a large number of organic dyes may also be used as sensitizers. Photosensitizers are a key component of photodynamic therapy used to treat cancers.

Recently use of Cerenkov luminescence (CL) with nanotechnology has been topic of a publication in Nature Nanotechnology by Shaffer et al. (7-2-2017), especially in view of imaging. Nanoparticles are described in combination with certain Cerenkov luminescence compounds for fluorescence imaging. Nanoparticles are considered best suited for use with CL given their high optical cross-sections compared with single smallmolecule fluorophores. Examples of images obtained from experiments on mice are given. CL has also been subject of two patent applications having inventors in common. US2017007724 (Al) and W02017019520 (Al) describe a two-component method, one component being a Cerenkov radiation sensitive component that may contain active payload, whereas the other component being a Cherenkov radiation emitting component. Therein the payload carrying component is the targeted component. The doc uments are focused on illumination with 18F. These method are found not to be very effective, for instance as a chance that the pay-load is released is too small. In addition only inactive compounds can be delivered, as a blocking agent is required. Also the radiation emitting compound has to be delivered at or near (<lmm) of the tumor, which is typically impossible or not feasible. In addition it is noted that the present inventors have found that the imaging compounds used are not stable under light conditions and in addition that these compounds do not dissolve very well and therefore can not be applied. A controlled release of payload is at least cumbersome. It is noted that for imaging Cerenkov nuclides have limited applicability in view of absorption by tissue. It suffers from all the drawbacks of optical imaging (reduced penetration depth and complex transport in tissue), with additional limitations due to the broader emission spectrum and to the nonlinear correlation with the distribution of the primary source responsible of the Cerenkov emission.

The present invention relates to a kit of parts, a medicament comprising said kit of parts, and a method of treating a disease by administering said kit of parts, which overcome one or more of the above disadvantages, without jeopardizing functionality and advantages.

SUMMARY OF THE INVENTION

The present invention relates in a first aspect to a kit of parts according to claim 1. The above two patent documents do not describe a radiation emitting component itself as a targeted component, and also important they do not describe Cerenkov radiation to trigger release of the payload; instead the payload is targeted to a cell. It is now found that significantly less payload, especially a drug or medicament can be used to be as effective as in the prior art. In addition payload can be administered a few sequential times, wherein e.g. the ß-particle emitting radionuclide remains active over time; therewith a concentration of active compounds can be much lower as well. Also for the above prior art methods typically an injection into a tumour is used, as the radiation needs to be provided close to a tumour, which is not necessary with the present kit and method. The present kit thereto comprises a first solution, typically an aqueous solution, which is to be administered separately from a second solution, also typically an aqueous solution. The first solution comprises a radionuclide coupled to a targeting agent. The radionuclide is typically non-toxic to a human or animal body. The radionuclide-targeting agent finds its way, after administration, through the body towards an intended cell receptor to which the targeting agent binds chemically. The radionuclide is capable of generating Cerenkov radiation, i.e. photons, upon release of e.g. a ß-particle. Specific radionuclides are found suitable, such as 13N, 150, 18F, 24Na, 28A1, 31Si, 32P, 37S, 38C1, 42K, 47Ca, 49Ca, 44Sc, 47Sc, 51Ti, 56Mn, 60Co, 62Cu, 64Cu, 67Cu, S8Ga, S8Ge, 71Zn, 70Ga, 72Ga, 75Ge, 76As, 81Se, 82Rb, 83Se, 86Rb, 87Kr, 88Rb, 83Sr, 83Zr, 90Y, 95Zr, "Mo, 105Ru, 110Ag, lllmPd, rilPd, lriAg, 114In, 123Sn, 124In, 125Sn, 127Te, 126I, 128I, 131If 137Xe, 135Xe< 133^, 140La< 141La, 141Ce< 142ρΓ/ 149Nd< isiNd, 153Sm, 155Sm, 152Eu, 154Eu, 153Gd, 160Tb, 1S5Dy, 16SDy, 1S6Ho, 172Er, 177Yb, 177Lu, 186Re, 187W, 188Re, 1910s, 192Ir, 194Ir, 137Pt, 198Au, 210Bi, 212Bi, 213Bi, 223Ra, 227Th, and daughters of 225Ac, preferably 13N, 150, 32P, 60Co, 62Cu, 68Ga, 68Ge, 86Rb, 89Sr, 89Zr, 30Y, 114In, 124In, 166Ho, 186Re, 188Re, 212Bi, 213Bi, 223Ra, and daughters of 225Ac. These radionuclides are found to give a good release of the therapeutic compounds, especially the preferred ones. Therewith only minute quantities of radionuclide are found to be required in view of an effective therapy. Such is a big advantages as side-effects of therapeutic compounds, side-effects typically being present, are largely mitigated. It is noted that the radionuclide may be provided as a mixture of isotopes of the same chemical element; only the relevant isotopes are included in the above quantity of 10“12-10“e gr/1. The second solution comprises a relatively small amount of vehicle, typically 10_4-101 gr/1. The vehicle comprises 10~5-10° gr/gr of at least one therapeutic compound which is incorporated therein, such as enclosed, largely or fully surrounded by the vehicle, bound to the vehicle, forming part of the vehicle, such as a chemical entity thereof, and combinations thereof. The vehicle further comprises 10~7-10_1 gr/gr of at least one photo-sensitizer, wherein the photo-sensitizer is incorporated in the vehicle or forms part of the vehicle, such as in the form of a chemical moiety. The at least one photosensitizer can be activated by a photon. When the vehicle is in the neighbourhood of the present radionuclide, which is (previously) attached to a cell by the targeting agent, a photon that originates from radionuclide as Cerenkov radiation can activate the photo-sensitizer. The photo-sensitizer initiates a structural change in the vehicle, which structural change can be a chemical change, a physical change, a partly or fully decomposition of the vehicle, and combinations thereof. By changing the structure of the vehicle the therapeutic compound is released at an intended location in the body and becomes effective at said location. Such is particularly suited for small sized tumours to be treated and metastases of tumours .

The present kit of parts may be used in the manufacture of a medicament, such as a medicament for treatment of cancer, treatment of metastases, such as deeply located metastases and not-identified metastases. Likewise the present invention relates to a medicament comprising said kit of parts.

In a further aspect the present invention relates to a method of treating of a disease, in particular a cancer or métastasé, comprising providing 0.1-5 ml/kg of the present second solution with the vehicle, administering 0.1-5 ml/kg of a first solution of the present invention with radionuclide coupled to a targeting agent for a tumour cell receptor, coupling the targeting agent to a tumour cell receptor, and activating the vehicle for release of the at least one therapeutic compound, preferably using timed sequential administration, such as with an idle time in between the provisions of 30 min-72 hours, such as 60 min-24 hours. The solutions are preferably administered intravenous, intratoneal, peritoneal, and subcutaneous .

Thereby the present invention provides a solution to one or more of the above mentioned problems.

Advantages of the present invention are detailed throughout the description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates in a first aspect to a kit of parts according to claim 1.

In an exemplary embodiment of the present kit the targeting agent is able to bind to a cell receptor, such as a tumour cell receptor, such as a cell surface receptor. Exemplary receptors are ion channel linked receptor, such as cys-loop receptors, ionotropic glutamate receptors and ATP-gated channels, an enzyme-linked receptor, such as an Erb receptor, such as ErbBl, ErbB2, ErbB3, and ErbB4, a GDNF receptor, such as GFRal, GFRa2, GFRa3, and GFRa4, a NPR receptor, such as NPR1, NPR2, NPR3, and NPR4, a trk neurotrophin receptor, such as TrkA, TrkB, TrkC, and p75, and a toll-like receptor, such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, and TLR 10, and a G protein-coupled receptor, such as a rhodopsin-like receptor, such as chemokine (C-C motif) receptor 1, chemokine (C-C motif) receptor 2, chemokine (C-C motif) receptor 3, chemokine (C-C motif) receptor 4, chemokine (C-C motif) receptor 5, chemokine (C-C motif) receptor 6, chemokine (C-C motif) receptor 7, chemokine (C-C motif) receptor 8, chemokine (C-C motif) receptor 9, chemokine (C-C motif) receptor 10, chemokine (C-C motif) receptor-like 1, chemokine (C-C motif) receptor-like 2, chemokine (C motif) receptor 1, chemokine (C-X3-C motif) receptor 1, chemokine (C-X3-C motif) receptor 3, chemokine (C-X3-C motif) receptor 4, chemokine (C-X3-C motif) receptor 5, chemokine (C-X3-C motif) receptor 6, chemokine (C-X3-C motif) receptor 7, GPR137B, IL8R-alpha, IL8R-beta, andrenomedullin receptor, duffy blood group chemokine receptor, G protein-coupled receptor 30, angiotensin II receptor type 1, angiotensin II receptor type 2, apelin receptor, bradykinin receptor Bl, bradykinin receptor B2, GPR15, GPR25, delta opioid receptor, kappa opioid receptor, mu opioid receptor, Nociceptin receptor, somatostatin receptor 1, somatostatin receptor 2, somatostatin receptor 3, somatostatin receptor 4, somatostatin receptor 5, neuropeptides B/W receptor 1, neuropeptides B/W receptor 2, galanin receptor 1, galanin receptor 2, galanin receptor 3, relaxin/insulin-like family peptide receptor 1, relaxin/insulin-like family peptide receptor 2, relaxin/insulin-like family peptide receptor 3, relaxin/insulin-like family peptide receptor 4, KiSSl-derived peptide receptor, melanin-concentrating hormone receptor 1, uro-tensin-II receptor, cholecystokinin A receptor, cholecystokin in B receptor, neuropeptide FF receptor 1, neuropeptide FF receptor 2, hypocretin receptor 1, hypocretin receptor 2, arginine vasopressin receptor 1A, arginine vasopressin receptor IB, arginine vasopressin receptor 2, gonadotrophin releasing hormone receptor, pyroglutamylated RFamide peptide receptor, bombesin-like receptor 3, neuromedin B receptor, gastrinreleasing peptide receptor, endothelin receptor type A, endo-thelin receptor type B, GPR37, neuromedin U receptor 1, neuromedin U receptor 2, neurotensin receptor 1, neurotensin receptor 2, thyrotropin-releasing hormone receptor, growth hormone secretagogue receptor, Motilin receptor, C3a receptor, C5a receptor, chemokine-like receptor 1, formyl peptide receptor 1, formyl peptide receptor-like 1, formyl peptide receptor-like 2, MASI, MAS1L, GPR1, GPR32, tachykinin receptor 1, tachykinin receptor 2, tachykinin receptor 3, neuropeptide Y receptor Yl, neuropeptide Y receptor Y2, pancreatic polypeptide receptor 1, neuropeptide Y receptor Y5, prolactinreleasing peptide receptor, prokineticin receptor 1, prokinet-icin receptor 2, GPR19, GPR50, FSH-receptor, luteinizing hor-mone/choriogonadotropin receptor, thyrotropin receptor, mela-nocortin 1 receptor, melanocortin 3 receptor, melanocortin 4 receptor, melanocortin 5 receptor and a ACTH receptor. Preferably the receptor is a receptor that, compared to non-tumour cells, is expressed more abundant at a tumour cell. Therewith very specific and effective binding of the targeting agent and radionuclide coupled thereto is achieved.

In an exemplary embodiment of the present kit the targeting agent is selected from a peptide or protein that is able to bind to a cell receptor. Examples thereof are epidermal growth factor, glial cell-derived neurotrophic factor, natriuretic peptide, a neurotropin, such as nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neuro-trophin-4, a microbial peptide or protein ligand, a chemokine, such as a chemokine, such as a homeostatic chemokine, such as CCL14, CCL19, CCL20, CCL21, CCL25, CCL27, CXCL12 and CXCL13, and an inflammatory chemokine, such as CXCL8, CCL2, CCL3, CCL4, CCL5, CCL11 and CXCL10, andrenomedullin, an angiotensin, such as angiotensin I, angiotensin II, angiotensin III and angiotensin IV, apelin, bradykinin, an opioid peptide, such as an enkephalin, an endophin and an dynorpin, nociceptin, a neuropeptide, such as galanin, somatostatin, neuropeptide Y, cholecystokinin, vasoactive intestinal peptide, a tachykinin peptide, such as neurokinin A and neurokinin K, neuropeptide gamma, and substance P, neurotensin, glucagon-like peptide-1, hypocretin and thyrotropin-releasing hormone, relaxin, insulin, kisspeptin, melanin-concentrating hormone, urotensin-II, vasopressin, gonadotrophin, bombesin, neuromendin B, neuromendin U, gastrin, endothelin, growth hormone, a growth hormone secretagogue, such as ghrelin, pralmorelin, GHRP-6, examorelin, ipamorelin, ibutamoren, growth hormone-releasing hormone, CJC-1295, sermorelin, and tesamorelin, motilin, C3a, C5a, an N-formyl peptide, chemerin, pancreatic polypeptide, prolactin-releasing peptide, prokineticin, follicle-stimulating hormone, luteinizing hormone, choriogonadotropin, thyrotropin and a melanocortin, such as adrenocorticotropic hormone and a melanocyte-stimulating hormone.

In an exemplary embodiment of the present kit the radionuclide is selected from 13N, 150, 32P, 62Cu, 68Ga, 68Ge, 86Rb, 89Sr, S0Y, 114In, 166Ho, 188Re, 212Bi, 213Bi, 223Ra, daughters of 225Ac, and 227Th, preferably 150, 32P, 62Cu, 68Ga, 68Ge, S6Rb, 89Sr, 90γ, 166Ho, 188Re, 212Bi, 223Ra, and 227Th, more preferably 150, e2Cu, 68Ga, 68Ge, 86Rb, S0Y, 114In, 166Ho, 188Re, and 212Bi, even more preferably 62Cu, 68Ga, 68Ge, 8SRb, 9CY, 114In, 166Ho, and 188Re, such as 68Ga and 82Rb. These radionuclides activate the present photo-sensitizer well and therewith establish an effective release of the present therapeutic compound.

In an exemplary embodiment of the present kit the vehicle is selected from nano-carriers and micro-carriers, such as microspheres, liposomes, polymerosomes, micelles, silica, hybrid particles, dendrimers, carbon nanoparticles, such as fullerenes, inorganic particles, such as hydrophobic-hydrophilic block-copolymer micelles, such as azobenzene comprising block-copolymers, such as a copolymer of poly(tertbutyl acrylate-coacrylic acid) and polymethacrylate bearing azobenzene, poly (ethylene oxide) (PEO) as the hydrophilic block and a polymethacrylate bearing spiropyran moieties as the hydrophobic block, and combinations thereof. The nanocarriers typically have a cross-section of 10-500 nm, whereas the micro-carriers typically have a cross-section of 0.5-100 pm. They may relates to organic molecules, such as liposomes, polymerosomes, etc. and be of inorganic type, such as silica, and combinations thereof. The vehicles can be loaded with a therapeutic compound by using a chemical technique, such as absorption of the therapeutic compound being present in a liquid, and by physical techniques, such as deposition of the therapeutic compound on the vehicle.

In an exemplary embodiment of the present kit the vehicle comprises a layer, which layer is adapted to at least partly disintegrate or undergo a structural change upon direct or indirect activation by the photo-sensitizer. The change may relate to a transition from e.g. a hydrophilic to a hydrophobic state, to an opening of the layer, to disruption of chemical bonds, resulting in the release of the therapeutic compound. The layer may have a thickness of 10-10000 nm.

In an exemplary embodiment of the present kit the photo-sensitizer comprises at least one of an aromatic ring, such as 1-5 aromatic rings, a conjugated double bond, a conjugated triple bond, a C=N bond, a isomeric changeable C=C cis or trans bond, such as violanthrone, isoviolanthrone, fluorescein, rubrene, 9,10-diphenylanthracene, tetracene, 13,13'-dibenzantronile, acrylcarbonylmethyl, nitrtoaryl, coumarin, arylmethyl, and levulinic acid. The present photo-sensitizer (PS) preferably absorbs light in the wavelength region of 180-500 nm, such as 200-360 nm, it provides a high singlet oxygen quantum yield, the excited triplet state has a long lifetime to allow for sufficient interaction between ground state oxygen and excited PS, it has a high resistance to photobleaching, it has a high resistance to oxidation by 1O2, the energy of the excited triplet state (difference between the Ti and the So state) is > 94 kJ/mole, which is the energy required to convert ground state oxygen to -‘-Cy, and is non-toxic, metabolizable and inert. In addition at neutral or slightly acidic/basic conditions (pH 5-9) the PSs preferably do not aggregate, such as in concentrations of 10-500 mM. Good examples are phenalenone and chlorin e6.

In an exemplary embodiment of the present kit the photo-sensitizer produces a singlet oxygen, is cleavable by a UV-photon, or initiates a cis-trans transition.

In an exemplary embodiment of the present kit the at least one therapeutic compound is incorporated in a nanocarrier, such as a nano-carrier or micro-carrier identified above .

In an exemplary embodiment of the present kit the therapeutic compound is selected from at least one of medicaments, drugs, chemotherapeutics, genes, metabolic active compound (TBC), and antibiotics, or a derivative thereof, or an analogue thereof. Also pro-drugs may be considered. In an exemplary embodiment of the present kit the drug is selected from cancer drugs, and cardio drugs. Examples of these drugs are cancer drugs, such as Abiraterone Acetate, Abitrexate or Methotrexate, Abraxane, Adcetris or Brentuximab Vedotin, Ado-Trastuzumab Emtansine, Adriamycin or Doxorubicin Hydrochloride, Afatinib Dimaleate, Afinitor or Everolimus, Akynzeo or Netupitant and Palonosetron Hydrochloride, Aldara or Imiquimod, Aldesleukin, Alecensa or Alectinib, Alectinib, Alemtuzumab, Alkeran for Injection or Melphalan Hydrochloride, Alkeran Tablets or Melphalan, Alimta or Pemetrexed Disodium, Aloxi or Palonosetron Hydrochloride, Ambochlorin or Chlorambucil, Amboclorin or Chlorambucil, Amifostine, Aminolevulinic Acid, Anastrozole, Aprepitant, Aredia or Pamidronate Disodium, Arimidex or Anastrozole, Aromasin or Exemestane, Arranon or Nelarabine, Arsenic Trioxide, Arzerra or Ofatumumab, Asparaginase Erwinia chrysanthemi, Atezolizumab, Avastin or Bevacizumab, Avelumab, Axitinib, Azacitidine, Bavencio or Avelumab, BEACOPP, Becenum or Carmustine, Beleodaq or Belinostat, Beli-nostat, Bendamustine Hydrochloride, BEP, Bevacizumab, Bexarotene, Bexxar or Tositumomab and Iodine I 131 Tositumomab, Bi-calutamide, BiCNU or Carmustine, Bleomycin, Blinatumomab, Blincyto or Blinatumomab, Bortezomib, Bosulif, Bosutinib, Brentuximab Vedotin, BuMel, Busulfan, Busulfex, Cabazitaxel, Cabometyx, Cabozantinib-S-Malate, Campath or Alemtuzumab, Camptosar or Irinotecan Hydrochloride, Capecitabine, Carac or Fluorouracil--Topical, Carboplatin, CARBOPLATIN-TAXOL, Carfil-zomib, Carmubris, Carmustine, Casodex or Bicalutamide,

Ceritinib, Cerubidine or Daunorubicin Hydrochloride, Cervarix or Recombinant HPV Bivalent Vaccine, Cetuximab, Chlorambucil, CHLORAMBUCIL-PREDNISONE, Cisplatin, Cladribine, Clafen or Cyclophosphamide, Clofarabine, Clofarex, Clolar, Cobimetinib, Cometriq or Cabozantinib-S-Malate, COPDAC, COPP, COPP-ABV, Cosmegen or Dactinomycin, Cotellic or Cobimetinib, Crizotinib, CVP, Cyclophosphamide, Cyfos or Ifosfamide, Cyramza or Ramu-cirumab, Cytarabine, Cytarabine Liposome, Cytosar-U or Cytarabine, Cytoxan or Cyclophosphamide, Dabrafenib, Dacarbazine, Dacogen or Decitabine, Dactinomycin, Daratumumab, Darzalex, Dasatinib, Daunorubicin Hydrochloride, Decitabine, Defibrotide Sodium, Defitelio, Degarelix, Denileukin Diftitox, Denosumab, DepoCyt or Cytarabine Liposome, Dexamethasone, Dexrazoxane Hydrochloride, Dinutuximab, Docetaxel, Doxil or Doxorubicin Hydrochloride Liposome, Doxorubicin Hydrochloride, Doxorubicin Hydrochloride Liposome, DTIC-Dome or Dacarbazine, Efudex or Fluorouracil--Topical, Elitek or Rasburicase, Ellence or Epi-rubicin Hydrochloride, Elotuzumab, Eloxatin or Oxaliplatin, Eltrombopag Olamine, Emend or Aprepitant, Empliciti or Elotuzumab, Enzalutamide, Epirubicin Hydrochloride, EPOCH, Erbitux or Cetuximab, Eribulin Mesylate, Erivedge or Vismodegib, Erlotinib Hydrochloride, Erwinaze or Asparaginase Erwinia chrysanthemi, Ethyol or Amifostine, Etopophos or Etoposide Phosphate, Etoposide, Etoposide Phosphate, Evacet or Doxorubicin Hydrochloride Liposome, Everolimus, Evista or Raloxifene Hydrochloride, Evomela or Melphalan Hydrochloride, Exemestane, 5-FU or Fluorouracil Injection, 5-FU or Fluorouracil--Topical, Fareston or Toremifene, Farydak or Panobinostat, Faslodex or Fulvestrant, Femara or Letrozole, Filgrastim, Fludara or Fludarabine Phosphate, Fludarabine Phosphate, Fluoroplex, Fluorouracil Injection, Fluorouracil—Topical, Flutamide, Fo-lex, Folex PFS, FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, Folotyn or Pralatrexate, FU-LV, Fulvestrant, Gardasil or Recombinant HPV Quadrivalent Vaccine, Gardasil 9 or Recombinant HPV Nonavalent Vaccine, Gazyva or Obinutuzumab, Gefitinib, Gemcitabine Hydrochloride, GEMCITABINE-CISPLATIN, GEMCITABINE-OXALIPLATIN, Gemtuzumab Ozogami-cin, Gemzar or Gemcitabine Hydrochloride, Gilotrif or Afat-inib Dimaleate, Gleevec or Imatinib Mesylate, Gliadel or

Carmustine Implant, Gliadel wafer or Carmustine Implant, Glu-carpidase, Goserelin Acetate, Halaven or Eribulin Mesylate, Hemangeol or Propranolol Hydrochloride, Herceptin or Trastuzumab, HPV Bivalent Vaccine, Recombinant HPV Nonavalent Vaccine, Recombinant HPV Quadrivalent Vaccine, Recombinant Hycamtin or Topotecan Hydrochloride, Hydrea, Hydroxyurea, Hy-per-CVAD, Ibrance or Palbociclib, Ibritumomab Tiuxetan Ibru-tinib, Iclusig or Ponatinib Hydrochloride, Idamycin, Idarubi-cin Hydrochloride, Idelalisib, Ifex, Ifosfamide, Ifosfamidum, IL-2 or Aldesleukin, Imatinib Mesylate, Imbruvica or Ibru-tinib, Imiquimod, Imlygic or Talimogene Laherparepvec, Inlyta or Axitinib, Interferon Alfa-2b, Recombinant Interleukin-2 or Aldesleukin, Intron A or Recombinant Interferon Alfa-2b, Iodine I 131 Tositumomab and Tositumomab, Ipilimumab, Iressa or Gefitinib, Irinotecan Hydrochloride, Irinotecan Hydrochloride Liposome, Istodax or Romidepsin, Ixabepilone, Ixazomib Citrate, Ixempra or Ixabepilone, Jakafi or Ruxolitinib Phosphate, Jevtana or Cabazitaxel, Kadcyla or Ado-Trastuzumab Emtansine, Keoxifene or Raloxifene Hydrochloride, Kepivance or Palifer-min, Keytruda or Pembrolizumab, Kisqali or Ribociclib, Kypro-lis or Carfilzomib, Lanreotide Acetate, Lapatinib Ditosylate, Lartruvo or Olaratumab, Lenalidomide, Lenvatinib Mesylate, Lenvima or Lenvatinib Mesylate, Letrozole, Leucovorin Calcium,

Leukeran or Chlorambucil, Leuprolide Acetate, Leustatin or Cladribine, Levulan or Aminolevulinic Acid, Linfolizin or Chlorambucil, LipoDox or Doxorubicin Hydrochloride Liposome, Lomustine, Lonsurf or Trifluridine and Tipiracil Hydrochloride, Lupron or Leuprolide Acetate, Lupron Depot or Leuprolide Acetate, Lupron Depot-Ped or Leuprolide Acetate, Lynparza or Olaparib, Marqibo or Vincristine Sulfate Liposome, Matulane or Procarbazine Hydrochloride, Mechlorethamine Hydrochloride, Megestrol Acetate, Mekinist or Trametinib, Melphalan, Melpha-lan Hydrochloride, Mercaptopurine, Mesna, Mesnex, Methazolas-tone or Temozolomide, Methotrexate, Methotrexate LPF, Methylnaltrexone Bromide, Mexate, Mexate-AQ, Mitomycin C, Mitoxan-trone Hydrochloride, Mitozytrex, Mozobil or Plerixafor, Mus-targen or Mechlorethamine Hydrochloride, Mutamycin or Mitomycin C, Myleran or Busulfan, Mylosar or Azacitidine, Mylotarg or Gemtuzumab Ozogamicin, Navelbine or Vinorelbine Tartrate,

Necitumumab, Nelarabine, Neosar or Cyclophosphamide, Netupi-tant and Palonosetron Hydrochloride, Neulasta or Pegfilgrastim, Neupogen or Filgrastim, Nexavar or Sorafenib Tosylate, Nilandron, Nilotinib, Nilutamide, Ninlaro or Ixazomib Citrate, Nivolumab, Nolvadex or Tamoxifen Citrate, Nplate or Romiplostim, Obinutuzumab, Odomzo or Sonidegib, Ofatumumab, Olaparib, Olaratumab, Omacetaxine Mepesuccinate, Oncaspar or Pegaspargase, Ondansetron Hydrochloride, Onivyde or Irinotecan Hydrochloride Liposome, Ontak or Denileukin Diftitox, Opdivo or Nivolumab, Osimertinib, Oxaliplatin, Paclitaxel, Palbo-ciclib, Palifermin, Palonosetron Hydrochloride, Netupitant, Pamidronate Disodium, Panitumumab, Panobinostat, Paraplat or Carboplatin,Pazopanib Hydrochloride, PCV, PEB, Pegaspargase Pegfilgrastim, Peginterferon Alfa-2b, PEG-Intron, Pembroli-zumab, Pemetrexed Disodium, Perjeta, Pertuzumab, Platinol or Cisplatin, Platinol-AQ, Plerixafor, Pomalidomide, Pomalyst, Ponatinib Hydrochloride, Portrazza or Necitumumab, Pralatrex-ate, Prednisone, Procarbazine Hydrochloride, Proleukin or Aldesleukin, Prolia or Denosumab, Promacta or Eltrombopag Olamine, Propranolol Hydrochloride, Provenge or Sipuleucel-T, Purinethol or Mercaptopurine, Purixan, Radium 223 Dichloride, Raloxifene Hydrochloride, Ramucirumab, Rasburicase, R-CHOP, R-CVP, Recombinant drugs, Recombinant Human Papillomavirus or HPV, Bivalent Vaccine, Recombinant Human Papillomavirus or HPV, Nonavalent Vaccine, Recombinant Human Papillomavirus or HPV, Quadrivalent Vaccine, Recombinant Interferon Alfa-2b, Regorafenib, Relistor or Methylnaltrexone Bromide, R-EPOCH, Revlimid or Lenalidomide, Rheumatrex or Methotrexate, Ribo-ciclib, R-ICE, Rituxan or Rituximab, Rituximab, Rolapitant Hydrochloride, Romidepsin, Romiplostim, Rubidomycin or Dauno-rubicin Hydrochloride, Rubraca, Rucaparib Camsylate, Rux-olitinib Phosphate, Sclerosol Intrapleural Aerosol, Siltuxi-mab, Sipuleucel-T, Somatuline Depot or Lanreotide Acetate, Sonidegib, Sorafenib Tosylate, Sprycel or Dasatinib, STANFORD V, Stivarga or Regorafenib, Sunitinib Malate, Sutent or Sunitinib Malate, Sylatron or Peginterferon Alfa-2b, Sylvant or Siltuximab, Synribo or Omacetaxine Mepesuccinate, Tabloid or Thioguanine, Tafinlar or Dabrafenib, Tagrisso or Osimertinib, Talc, Talimogene Laherparepvec, Tamoxifen Citrate, Tar- abine PFS or Cytarabine, Tarceva or Erlotinib Hydrochloride, Targretin or Bexarotene, Tasigna or Nilotinib, Taxol or Paclitaxel, Taxotere or Docetaxel, Tecentriq or Atezolizumab, Temodar or Temozolomide, Temozolomide, Temsirolimus, Thalidomide, Thalomid or Thalidomide, Thioguanine, Thiotepa, Tolak or Fluorouracil--Topical, Topotecan Hydrochloride, Toremifene, Torisel or Temsirolimus, Tositumomab and Iodine I 131 Tosi-tumomab, Totect or Dexrazoxane Hydrochloride, Trabectedin, Trametinib, Trastuzumab, Treanda or Bendamustine Hydrochloride, Trifluridine and Tipiracil Hydrochloride, Trisenox or Arsenic Trioxide, Tykerb or Lapatinib Ditosylate, Unituxin or Dinutuximab, Uridine Triacetate, Vandetanib, Varubi or Rolapi-tant Hydrochloride, Vectibix or Panitumumab, VelP, Velban or Vinblastine Sulfate, Velcade or Bortezomib, Velsar or Vinblastine Sulfate, Vemurafenib, Venclexta or Venetoclax, Veneto-clax, Viadur or Leuprolide Acetate, Vidaza or Azacitidine, Vinblastine Sulfate, Vincasar PFS or Vincristine Sulfate, Vincristine Sulfate, Vincristine Sulfate Liposome, Vinorelbine Tartrate, Vismodegib, Vistogard or Uridine Triacetate, Voraxa-ze or Glucarpidase, Vorinostat, Votrient or Pazopanib Hydrochloride, Wellcovorin or Leucovorin Calcium, Xalkori or Crizo-tinib, Xeloda or Capecitabine, XELIRI, XELOX, Xgeva or Deno-sumab, Xofigo or Radium 223 Dichloride, Xtandi or Enzalutam-ide, Yervoy or Ipilimumab, Yondelis or Trabectedin, Zaltrap or Ziv-Aflibercept, Zarxio or Filgrastim, Zelboraf or Vemurafenib, Zevalin or Ibritumomab Tiuxetan, Zinecard or Dexrazoxane Hydrochloride, Ziv-Aflibercept, Zofran or Ondansetron Hydrochloride, Zoladex or Goserelin Acetate, Zoledronic Acid, Zolinza or Vorinostat, Zometa or Zoledronic Acid, Zydelig or Idelalisib, Zykadia or Ceritinib, Zytiga or Abiraterone Acetate, in particular docetaxel, doxorubicin, paclitaxel, cisplatin, capox, carboplatin, Carfilzomib, Rucaparib, and Cam-sylate, cardio drugs, such as agents for hypertensive emergencies, for pulmonary hypertension, aldosterone receptor antagonists, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor blockers, neprilysin inhibitors, for antiadrenergy, for centrally acting antiadren-ergy, for peripherally acting antianginal, for antiarrhyth-mics, such as so-called group I antiarrhythmics, group II an- tiarrhythmics, group III antiarrhythmics, group IV antiarrhythmics, and group V antiarrhythmics, for anticholinergic chronotropy, for antihypertensive combinations, such as ACE inhibitors and calcium channel blocking, ACE inhibitors with thiazides, angiotensin II inhibitors and calcium channel blockers, angiotensin II inhibitors and thiazides, for antiad-renergy or central, and thiazides, for antiadrenergic or peripheral, and thiazides, beta blockers and thiazides, for potassium sparing diuretics and thiazides, for beta-adrenergy blocking, such as cardio selective beta blockers, and non-cardio selective beta blockers, for calcium channel blocking, catechol amines, diuretics, such as carbonic anhydrase inhibitors, loop diuretics, miscellaneous diuretics, potassium-sparing diuretics, thiazide diuretics, for inotropy, peripheral vasodilators, renin inhibitors, for sclerosy, vasodilators, vasopressin antagonists, vasopressors, and antibiotics, such as aminoglycosides, beta lactams, such as amoxicillin, car-bapenems, penicillins, cephalosporins, kanamycins, thienamy-cin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, sulfamethoxazole, trimethoprim, amoxicillin, clavulanate, levofloxacin, fosfomycins, mycines, such as amikacin, arbekacin, azithtromycin, butirosin, clarithromycin, dibekacin, erythromycin, kanamycin, Kanamycin A, Kanamycin B, Kanamycin C, Kanamycin D, Kanamycin X, 3"-Deamino-3"-hydroxykanamycin B, 3"-Deamino-3"-hydroxykanamycin C, 3"-Deamino-3"-hydroxykanamycin X, lividomycin, Nebramycin 57, , neomycin, neomycin B, neomycin C, neomycin E, ribostamy-cin, streptomycin, tobramycin, vancomycin, and micines, such as dexoystreptamine, geneticin, gentamicin, gentamicin A2, gentamicin Cl, gentamicin C2, gentamicin C18, isepamicin, netilmicin, and sisomicinazabicyclo[3.2.0]hept-2-ene-2-carboxylic acids, such as 7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acids, such as thienamycin ((5R,6S)-3-[(2-Aminoethyl)thio]-6-[(IR)-1-hydroxyethyl]-7-oxo-l-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid), imipenem (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-({2—[(iminomethyl)amino]-ethyl}thio )-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, meropenem 4R,5S,6S)-3-(((3S,5S)-5-(Dimethylcarbamoyl)-pyrrolidin-3-yl) thio)-6-( (R)-1-hydroxyethyl)-4-methyl-7-oxo-l- azabicyclo[3.2. O]hept-2-ene-2-carboxylic acid, ertapenem (4R,5S,6S)-3-[ (3S,5S)-5- [ (3-carboxyphenyl) carbamoyl] pyrroli-din-3-yl]sulfanyl-6-(1-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, doripenem (4R, 5S, 6S)-6-(1-Hydroxyethyl)-4-methyl-7-oxo-3-( ( (5S)-5-((suifamoy1amino)methyl)pyrrolidin-3-yl)thio )-1-azabicyclo-[3.2.0]hept-2-ene-2-carboxylic acid, panipenem/betamipron (5R,6S)-3-{[(3S)-l-ethanimidoylpyrrolidin-3-yl]sulfanyl}- 6-[(IR)-1-hydroxyethyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, biapenem (4R,5S,6S)-3-(6,7-dihydro-5H- pyra-zolo[l,2-a][1,2,4]triazol-8- ium-6-ylsulfanyl)- 6-(1-hydroxyethyl)- 4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate, razupenem (4R,5S,6S)-6-((R)-1-hydroxyethyl)-4-methyl-3-((4-((S)-5-methyl-2,5-dihydro-lH-pyrrol-3-yl)thiazol-2-yl) thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, tebipenem (4R, 5S, 6S)-(Pivaloyloxy)methyl 3-((1-(4,5-dihydrothiazol-2-yl)azetidin-3-yl)thio)-6-((R)-1-hydroxyethyl) -4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate, lenapenem, tomopenem ((4R,5S,6S)-3-[(3S,5S)-5-[ (3S)-3-[[2-(diaminomethylideneamino ) acetyl]amino]pyrrolidine-1-carbonyl]-l-methylpyrrolidin-3-yl]sulfanyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), or a derivative thereof, or an analogue thereof. Hence a large variety of therapeutic compounds can be administered and selected for a given purpose.

In an exemplary embodiment of the present kit the radionuclide produces photons with a maximum intensity at a wavelength of 180-500 nm, e.g. 200-360 nm. It has been found that especially these photons are effective in terms of structurally changing the present vehicle and as a result release of the therapeutic compound thereof.

In an exemplary embodiment of the present kit the radionuclide has a half life time of 5 min-28 days. The activity of the radionuclide is preferably not too low and also the activity is maintained over a prolonged period of time. For many applications the half life time is not very critical; for the present invention the half life time is limited in view of the administration of the therapeutic compound, which is released only upon (indirect) generation of photons by the present ra dionuclide. In this respect especially 13N, 32P, 62Cu, 68Ga, 8SRb, 89Sr, 90Y, 166Ho, 188Re, 212Bi, 213Bi, 223Ra, daughters of 225Ac, and 227Th are considered, preferably 32P, 68Ga, 90Y, 166Ho, 188Re, 212Bi, 213Bi, 223Ra, and daughters of 225Ac, more preferably 68Ga, 9CY, 16SHo, 188Re, and 212Bi, even more preferably S8Ga, 90Y, 166Ho, 188Re, such as 68Ga .

In an exemplary embodiment of the present kit the radionuclide is conjugated to the targeting agent, such as to a peptide. Therewith a stable bond is provided which is maintained over the life time of the radionuclide.

In an exemplary embodiment of the present kit the radionuclide dose is 0.1-200 Gy (J/kg = m2/s2), preferably 0.2-150 Gy, more preferably 1-100 Gy, even more preferably 5-80 Gy, such as 10-50 Gy or 20-40 Gy. Therewith both large doses (e.g. > 80 Gy, such as > 120 Gy) and small doses (e.g. < 1 Gy, such as < 0.5 Gy) can be provided; the present kit of parts is very versatile in this respect.

The invention is further detailed by the accompanying figures and examples, which are exemplary and explanatory of nature and are not limiting the scope of the invention. To the person skilled in the art it may be clear that many variants, being obvious or not, may be conceivable falling within the scope of protection, defined by the present claims .

SUMMARY OF THE FIGURES

Figure 1 shows schematics of the present invention.

DETAILED DESCRIPTION OF THE FIGURES

Figure 1 shows schematics of the present invention. It relates to a rather novel and original approach to tumor-targeted chemotherapy. Therein aspects of PDT in combination with targeted tumor delivery to release chemotherapeutic drugs only at the tumor are used, in particular enabling attack of deeply situated and unknown metastases with very limited side effects. Cerenkov radiation generated by radionuclides at the tumor is used as a source of UV-photons to activate chemotherapeutic agents. The Cerenkov radiation is essentially harmless UV light such as created by energetic ß-particles when transferring through a medium. The present Cerenkov radiation has a broad spectrum (Àmas~360 nm), which enables activation of UV active substances used in PDT. Certain ß-particle emitting radionuclides can have a very high yield of Cerenkov photons and are even currently employed in Cerenkov pre-clinical imaging. In an example these radionuclides are delivered to a tumor site by conjugation to certain peptides. There, the generated Cerenkov photons can initiate release of a chemotherapeutic agent. Radionuclides such as 68Ga, giving 34 photons per decay, may be used in diagnostics and show no adverse health effects (in fact they have a lower radiation dose than CT scans).

Two approaches are followed. In the first approach very stable nano-carriers such polymerases are used, where the UV active sensitizer is encapsulated or incorporated in the polymerosome membrane while in the lumen a drug is enclosed. When exposed to Cerenkov UV-photons, the sensitizer will produce highly reactive singlet oxygen species, which will destroy the membrane and therefore release the drug.

In the second approach so-called prodrugs are used, which are chemically inactivated drugs that can be activated by UV light. In their native form prodrugs are harmless and not effective. Reaction with Cerenkov radiation will locally activate the drug, killing the tumor cells. Potential prodrugs are O-nitrobenzyl-protected Doxorubicin and Auristatin E/F.

An important part of both approaches is that the drug release or activation is only triggered when exposed to the Cerenkov radiation coming from the radionuclide, which is located only at the tumor site. In both approaches, a combination of timed sequential administration of the radionuclide and the drug, and a difference in bio distribution, ensures that the radionuclide and the drug only meet at the tumor. The radionuclide is in an example coupled to a peptide, which peptide may also be used in selective tumor visualization, which peptide is typically cleared from the body in a few hours and has no accumulation in liver or spleen (clearance organs of nano-carriers) and short residence time in the kidneys. The nano-carrier or the prodrug is typically injected first, and is given sufficient time to achieve total elimination from the blood stream, after which the radionuclide bound to the peptide will be administered .

EXAMPLES/EXPERIMENTS

The invention although described in detailed explanatory context may be best understood in conjunction with the accompanying examples.

Production of singlet oxygen A singlet oxygen 4O2 is produced by 166Ho and 68Ga.

In contrast to normal ground state oxygen, 102 possesses a high reactivity and may readily react with unsaturated organic molecules. The reactivity of Me is found to strongly depend on its lifetime, which is mainly controlled by solvent properties; for instance in water a kinetic lifetime Ta of ~ 3.3 ps has been reported.

In general 4O2 can be produced via photochemical pathways by means of a photosensitizer (PS) molecule or via chemical sources, for example reaction of sodium hypochlorite with hydrogen peroxide. Suitable PSs are for instance tetraphenylpor-phyrin, Methylene blue and Rose Bengal. In the experiments further Phenalenone and Chlorin e6 were used. Phenalenone has an outstanding :02 quantum yield of 0.99 (H2O, 337-439 nm) and an extinction coefficient of 11250 M“1 cm“1 (MeOH, 360 nm) . Chlorin e6 has a smaller 4O2 quantum yield of 0.65 (EtOH, 347 nm) but a large extinction coefficient of 200000 M“1 cm“1 (EtOH, 401 nm). With regard to the Cherenkov spectrum, which has the highest intensity between 300 and 400 nm, Phenalenone covers a wider range of the radiation than Chlorin e6. Furthermore, the 1O2 quantum yield of Phenalenone is wavelengthindependent over a broad region (337-439 nm) .

Materials and methods

Chlorin e6 was purchased from Frontier Scientific. SOSG (Singlet Oxygen Sensor Green) was purchased from Thermo Fisher. Phenalenone, Acetonitrile, HEPES (4-(2-hydroxyethyl)piperazine-l-ethanesulfonic acid) and HoC13-6H20 (Holmium (111) chloride hexahydrate) were purchased from Sigma Aldrich. EDTA (Ethylenediaminetetraacetic acid) was purchased from Merck. Ultrapure water was prepared with the in-house

Milli-Q system from Merck Millipore. Measurements were conducted in UV transparent cuvettes by means of a Cary Eclipse Fluorescence Spectrophotometer from Agilent Technologies with the following settings: Velocity Fast, Medium detector voltage, Àex = 509 nm for SOSG*. The LED (400 nm) was purchased from Ledshighpower (Landgraaf, The Netherlands). In general, all operations were carried out under dark conditions.

Preparation of PSs

Glass vials were wrapped in aluminium foil and sealed with caps. Phenalenone was first dissolved in methanol and vortexed for 1 minute. Afterwards, it was further diluted in HEPES (100 mM) to reach a final concentration of 1 mM with 10% (v/v) methanol. Chlorin e6 was dissolved in HEPES (100 mM) to reach a final concentration of 100 μΜ. Afterwards, it was put in the ultrasonic bath for 30 minutes. In the experiments, the PSs were further diluted with HEPES (100 mM) to reach the desired concentration

Preparation of Singlet Oxygen Sensor Green (SOSG) SOSG was dissolved in methanol to reach a final concentration of 1.2 mM. In the experiments, SOSG was further diluted with HEPES (100 mM) to reach a final concentration of 6 μΜ.

Chlorin e6 exposed to LED light 2 ml of Chlorin e6 (10, 15, 20, 25, 30, 40 or 50 μΜ) together with SOSG were placed in a cuvette, subsequently sealed with a cap and exposed to the light source (2.8V, 0.75 A) mounted inside the fluorimeter. PSs exposed to Ho-166 2 ml of Chlorin e6 (20 μΜ) and Phenalenone (100 μΜ), respectively, together with SOSG were placed in a cuvette and positioned in the closed fluorimeter. HoC13-6H20 (3 mg) was activated in a nuclear reactor (Reactor Insitute Delft, The Netherlands, thermal neutron flux 3.1 X 1016 n s_1 m~2, 10 hours) . The activated Holmium salt (200 MBq) dissolved in 200 μΐ EDTA solution (65.9 mM in 100 mM HEPES) was added into the cuvette and sealed with a cap. Controls contained the same amount of non-activated Holmium salt.

Phenalenone exposed to Ga-68 2 ml of Phenalenone (100 μΜ) together with SOSG were placed in a cuvette and positioned in the closed fluorimeter. Ga-68 was eluted from a Ge-68/Ga-68 generator (Eckert & Ziegler) with 0.1 M HC1 in fractions of 0.5 ml. The fraction containing the highest activity (65 MBq) was added to a solution consisting of 500 μΐ HEPES (100 mM) , 50 μΐ NaOH (1 M) and 10 μΐ EDTA (65.9 mM in 100 mM HEPES).

The final mixture was added into the cuvette and sealed with a cap .

Results and Discussion

Chlorin e6 exposed to LED light

Chlorin e6 was exposed to LED light in the presence of SOSG. The production of 1O2 was tracked by measuring generated SOSG* via fluorescence spectrometry. It was found that a higher pH led to a decreased production of 4θ2. A control only containing SOSG without any PS did not cause any production of 4O2. It is noted that the reduced production of the oxygen species is attributed to the SOSG molecule itself and not to the PS. The fluorescence of the SOSG-probe is found very sensitive to pH changes. The highest production of 3O2 was found within a range of 15 - 20 μΜ PS. Further increase of the concentration led to aggregation of Chlorin e6, accompanied by a drop in production of the oxygen species. Chlorin e6 molecule starts to aggregate within the range of 15.1 - 16.8 μΜ at pH 7. Therefore, in all the following experiments a PS concentration of 20 μΜ at a pH of 7.4 was used.

Singlet oxygen produced by means of radioisotopes Photosensitizers were exposed to beta emitting radioisotopes to investigate whether the Cherenkov radiation is sufficient enough to produce 4O2. The production of the oxygen species was detected by means of SOSG. Generated SOSG* was measured using fluorescence spectrometry. During the research, it was noted that SOSG* completely disappeared in the presence of Ho3+ and could not be detected with the fluorimeter anymore. Only when the holmium salt was chelated with EDTA, SOSG* could still be measured.

Phenalenone and Chlorin e6 in the presence of SOSG were exposed to Ho-166. It was found that 4θ2 was produced, indicat ed by an increase of the intensity maximum of SOSG*. Controls containing no radioisotope but only the respective PS together with SOSG show that the absence of Cherenkov radiation did not lead to any oxygen species. Comparing the production rate of 1Û2 between Phenalenone (orange) and Chlorin e6 (blue) at 180 minutes, more than twice the amount of singlet oxygen was produced by Phenalenone. This can be explained by the high ^-02 quantum yield of Phenalenone (Φ ~ 1.0) and its absorption spectrum which covers a wider range of the Cherenkov radiation than Chlorin e6. In addition, Phenalenone was applied in a higher concentration than Chlorin e6 since it is not constrained to a certain concentration maximum. Higher concentrations (>100 μΜ, e.g. up to 500 μΜ) Phenalenone can be employed to increase production of 1O2.

Besides Ho-166, Phenalenone was exposed to the radioisotope Ga-68. In contrast to the beta minus emitting Ho-166, Ga-68 decays via beta plus emission. With regard to the photodynamic properties, Ga-68 emits 33.9 photons per decay, while Ho-166 only emits 27.5 photons per decay. The intensity of Ho-166 remains longer since its half-life time is almost 27 hours, while the half-life time of Ga-68 is only 67 minutes. It was found that the exposure of the PS to Ga-68 led to a production of the oxygen species, indicated by an increase of the intensity maximum of SOSG*. Comparing the 4O2 production caused by Ho-166 and Ga-68 at 150 minutes, more than twice the amount of 4O2 was produced by Ho-166. This can be explained by the difference in activities. Ga-68 was eluted from a Ge-68/Ga-68 generator with a final activity of 65 MBq, while the Holmium salt activated in the reactor had an activity of 200 MBq. The higher the activity, the more beta particles are emitted over time and the stronger the intensity of the Cherenkov radiation. Therefore, 200 MBq of Ho-166 led to a higher production rate of -1θ2 than 65 MBq Ga-68.

For the purpose of searching the following section is provided, of which the next section represents a translation into Dutch. 1. A kit of parts for providing a chemical compound to a cell, comprising a first solution comprising 1CF12-1O~6 gr/1 of at least one radionuclide coupled to a targeting agent for a cell receptor, wherein the radionuclide is capable of generating Cerenkov radiation, wherein the radionuclide is selected from 13N, 150, 18F, 24Na, 28A1, 31Si, 32P, 37S, 38C1, 42K, 47Ca, 49Ca, 44Sc, 47Sc, 51Ti, 56Mn, S0Co, S2Cu, S4Cu, 67Cu, 68Ga, 68Ge, 71Zn, 70Ga, 72Ga, 75Ge, 7eAs, 81Se, 82Rb, 83Se, 86Rb, 87Kr, 88Rb, 89Sr, 89Zr, 90Y, 95Zr, "Mo, 105Ru, 11 oAg, m™pd, rllPd, 711Ag, 114In, 123Sn, 124In, 125Sn, 127Te, 126I, 128I, 131I, 137Xe, 135Xe, 139Ba, 14üLa, 141La, 141Ce, 142Pr, 149Nd, 151Nd, 153Sm, 155Sm, 152Eu, 154Eu, 159Gd, 160Tb, 1S5Dy, 166Dy, 166Ho, 172Er, 177Yb, 177Lu, 186Re, 187W, 188Re, 1910s, 192Ir, 194Ir, 197Pt, 198Au, 210Bi, 212Bi, 213Bi, 223Ra, 227Th, and daughters of 225Ac, and a second solution comprising 10"4-101 gr/1 of a vehicle, the vehicle comprising 10“5-10° gr/gr of at least one therapeutic compound incorporated therein, and 10’7-10"1 gr/gr of at least one photo-sensitizer, wherein the photo-sensitizer is incorporated in the vehicle or forms part of the vehicle, which at least one photo-sensitizer can be activated by a photon, which photon originates from the radionuclide as Cerenkov radiation, which photo-sensitizer initiates a structural change in the vehicle thereby releasing the therapeutic compound, wherein all weights are relative to a total weight of the first or second solution, respectively, and wherein the weight of the radionuclide relates to radioactive species only. 2. Kit of parts according to embodiment 1, wherein the targeting agent is able to bind to a cell receptor, such as a tumour cell receptor, such as a cell surface receptor. 3. Kit of parts according to any of the preceding embodiments, wherein the targeting agent is a peptide or protein that is able to bind to a cell receptor. 4. Kit of parts according to any of the preceding embodiments, wherein the radionuclide is selected from 13N, 150, 32P, 62Cu, 68Ga, 68Ge, 86Rb, 89Sr, 9CY, 114In, 166Ho, 188Re, 212Bi, 213Bi, 223Ra, daughters of 225Ac, and 227Th, preferably from 68Ga and 82Rb. 5. Kit of parts according to any of the preceding embodiments, wherein the vehicle is selected from nano-carriers or micro-carriers, such as microspheres, liposomes, polymero-somes, micelles, silica, hybrid particles, dendrimers, carbon nanoparticles, such as fullerenes, inorganic particles, such as hydrophobic-hydrophilic block-copolymer micelles, such as azobenzene comprising block-copolymers, such as a copolymer of poly ( tert-butyl acrylate-coacrylic acid) and polymethacrylate bearing azobenzene, poly (ethylene oxide) (PEO) as the hydrophilic block and a polymethacrylate bearing spiropyran moie-ties as the hydrophobic block, and combinations thereof. 6. Kit of parts according to any of the preceding embodiments, wherein the vehicle comprises a layer, which layer is adapted to at least partly disintegrate or undergo a structural change upon direct or indirect activation by the photosensitizer . 7. Kit of parts according to any of the preceding embodiments, wherein the photo-sensitizer comprises at least one of an aromatic ring, such as 1-5 aromatic rings, a conjugated double bond, a conjugated triple bond, a C=N bond, a isomeric changeable C=C cis or trans bond, such as violanthrone, isovi-olanthrone, fluorescein, rubrene, 9,10-diphenylanthracene, tetracene, 13, 13'-Dibenzantronile, acrylcarbonylmethyl, ni-trtoaryl, coumarin, arylmethyl, and levulinic acid. 8. Kit of parts according to any of the preceding embodiments, wherein the photo-sensitizer produces a singlet oxygen, is cleavable by a UV-photon, or initiates a cis-trans transition . 9. Kit of parts according to any of the preceding embodiments, wherein the at least one therapeutic compound is incorporated in a nano-carrier. 10. Kit of parts according to any of the preceding embodiments, wherein the therapeutic compound is selected from at least one of medicaments, drugs, chemotherapeutics, genes, metabolic active compound (TBC), and antibiotics, or a derivative thereof, or an analogue thereof. 11. Kit of parts according to embodiment 10, wherein the drug is selected from cancer drugs, and cardio drugs. 12. Kit of parts according to any of the preceding embodiments, wherein the radionuclide produces photons with a maxi mum intensity at a wavelength of 180-500 nm, such as 200-360 nm. 13. Kit of parts according to any of the preceding embodiments, wherein the radionuclide has a half life time of 5 min-28 days. 14. Kit of parts according to any of the preceding embodiments, wherein the radionuclide is conjugated to the targeting agent, such as to a peptide or protein. 15. Kit of parts according to any of the preceding embodiments, wherein the radionuclide dose is 0.1-200 Gy (J/kg = im/sU . 16. Kit of parts according to any of embodiments 1-15 for use in the manufacture of a medicament, such as a medicament for treatment of cancer, treatment of metastases, such as deeply located metastases and not-identified metastases. 17. Medicament comprising a kit of parts according to any of embodiments 1-15. 18. Method of treating of a disease, comprising providing 0.1-5 ml/kg of a second solution according to any of embodiments 1-15 with the vehicle, administering 0.1-5 ml/kg of a first solution according to any of embodiments 1-14 with radionuclide coupled to a targeting agent for a tumour cell receptor, coupling the targeting agent to a tumour cell receptor, and activating the vehicle for release of the at least one therapeutic compound, preferably using timed sequential administration .

Claims

1. Een samenstel van onderdelen voor het verschaffen van een chemische verbinding aan een cel, omvattende een eerste oplossing omvattende 10~12-10~s gr/1 van ten minste één radionuclide gekoppeld aan een targetingmiddel voor een celreceptor, waarbij het radionuclide in staat is om Cerenkov-straling te genereren, waarbij het radionuclide is gekozen uit 13N, 150, 1SF, 24Na, 28A1, 31Si, 32P, 37S, 38C1, 42K, 47Ca, 49Ca, 44Sc, 47Sc, 51Ti, 56Mn, 60Co, 62Cu, 64Cu, 67Cu, 68Ga, 68Ge, 71Zn, 70Ga, 72Ga, 75Ge, 76As, 81Se, 82Rb, 83Se, 86Rb, 87Kr, 88Rb, 89Sr, 89Zr, S0Y, S5Zr, "Mo, 105Ru, 110Ag, lllmPd, inPd, 131Ag, 114In, 123Sn, 124In, 125Sn, 127Te, 12SI, 128I, 131I, 137Xe, 135Xe, 139Ba, 140La, 141La, 141Ce, 142Pr, 149Nd, 151Nd, 153Sm, 155Sm, 152Eu, 154Eu, 159Gd, 160Tb, 165Dy, 166Dy, 166Ho, 172Er, 177Yb, 177Lu, 186Re, 187W, 188Re, 1910s, 1S2Ir, 194Ir, 1S7Pt, 198Au, 210Bi, 212Bi, 213Bi, 223Ra, 227Th, en dochters van 225Ac, en een tweede oplossing die 10_4-101 gr/1 van een vehikel omvat, waarbij het vehikel 10“5-10° gr/gr van ten minste één the-rautische verbinding daarin omvat, en 10“7-10’1 gr/gr van ten minste één fotosensibilisator, waarbij de fotosensibilisator in het vehikel is opgenomen of deel uitmaakt van het vehikel, welke ten minste één fotosensibilisator kan worden geactiveerd door een foton, welke foton afkomstig is van het radionuclide als Cerenkovstraling, welke fotosensibilisator een structurele verandering in het vehikel initieert waardoor de therapeutische verbinding wordt vrijgegeven, waarbij alle gewichten betrokken zijn op een totaal gewicht van respectievelijk de eerste of tweede oplossing en waarbij het gewicht van het radionuclide alleen betrekking heeft op radioactieve species.An assembly of parts for providing a chemical compound to a cell, comprising a first solution comprising 10 ~ 12-10 ~ s gr / l of at least one radionuclide coupled to a cell receptor targeting agent, the radionuclide being capable of is to generate Cerenkov radiation, wherein the radionuclide is selected from 13N, 150, 1SF, 24Na, 28A1, 31Si, 32P, 37S, 38C1, 42K, 47Ca, 49Ca, 44Sc, 47Sc, 51Ti, 56Mn, 60Co, 62Cu, 64Cu, 67Cu, 68Ga, 68Ge, 71Zn, 70Ga, 72Ga, 75Ge, 76As, 81Se, 82Rb, 83Se, 86Rb, 87Kr, 88Rb, 89Sr, 89Zr, SOY, S5Zr, "Mo, 105Ru, 110Ag, 111mPd, inPdA ,PdA , 114In, 123Sn, 124In, 125Sn, 127Te, 12SI, 128I, 131X, 137Xe, 135Xe, 139Ba, 140La, 141La, 141Ce, 142Pr, 149Nd, 151Nd, 153Sm, 155Sm, 152Eu, 154Eu, 159Gd, 160Tb, 165Dy, 166Dy , 166Ho, 172Er, 177Yb, 177Lu, 186Re, 187W, 188Re, 1910s, 1S2Ir, 194Ir, 1S7Pt, 198Au, 210Bi, 212Bi, 213Bi, 223Ra, 227Th, and daughters of 225Ac, and a second solution containing 10-4-101 gr / 1 of a vehicle, wherein the vehicle comprises 10 "5-10 ° g / gr of at least one theoretical compound therein, and 10" 7-10 "1 g / gr of at least one photosensitizer, the photosensitizer being incorporated into the vehicle or forming part of the vehicle, which at least one photosensitizer can be activated by a photon, which photon comes from the radionuclide as Cerenkov radiation, which photosensitizer initiates a structural change in the vehicle whereby the therapeutic compound is released, all weights being based on a total weight of the first or second solution, respectively, and wherein the weight of the radionuclide relates only to radioactive species.

2. Samenstel van onderdelen volgens conclusie 1, waarbij het targetingsmiddel in staat is te binden aan een celreceptor, zoals een tumorcelreceptor, zoals een celoppervlakrecep-tor.The assembly of parts according to claim 1, wherein the targeting agent is capable of binding to a cell receptor, such as a tumor cell receptor, such as a cell surface receptor.

3. Samenstel van onderdelen volgens een der voorgaande conclusies, waarbij het targetingsmiddel een peptide of eiwit is dat in staat is te binden aan een celreceptor.The assembly of parts according to any of the preceding claims, wherein the targeting agent is a peptide or protein capable of binding to a cell receptor.

4. Samenstel van onderdelen volgens één der voorgaande conclusies, waarbij het radionuclide is gekozen uit 13N, 150, 32P, 62Cu, 68Ga, 68Ge, 86Rb, 89Sr, 90Y, 114In, 16SHo, 188Re, 212Bi, 213Bi, 223Ra, dochters van 225Ac, en 227Th, bij voorkeur uit 68Ga en 82Rb.The assembly of parts according to any of the preceding claims, wherein the radionuclide is selected from 13N, 150, 32P, 62Cu, 68Ga, 68Ge, 86Rb, 89Sr, 90Y, 114In, 16SHo, 188Re, 212Bi, 213Bi, 223Ra, daughters of 225Ac , and 227 Th, preferably from 68 Ga and 82 Rb.

5. Samenstel van onderdelen volgens een van de voorgaande conclusies, waarbij het vehikel is gekozen uit nano-dragers of micro-dragers, zoals microsferen, liposomen, polymerosomen, micellen, silica, hybride deeltjes, dendrimeren, koolstofnano-deeltjes, zoals fullerenen, anorganische deeltjes, zoals hy-drofobe-hydrofiele blokcopolymeermicellen, zoals azobenzeen omvattende blokcopolymeren, zoals een copolymeer van poly (tert-butylacrylaatcoacrylzuur) en azobenzeen-dragend polyme-thacrylaat, poly(ethyleenoxide) (PEO) als het hydrofiele blok en een polymethacrylaat die spiropyran delen draagt als het hydrofobe blok, en combinaties daarvan.The assembly of parts according to any of the preceding claims, wherein the vehicle is selected from nano-carriers or micro-carriers, such as microspheres, liposomes, polymerosomes, micelles, silica, hybrid particles, dendrimers, carbon nanoparticles, such as fullerenes, inorganic particles, such as hydrophobic-hydrophilic block copolymer micelles, such as azobenzene comprising block copolymers, such as a copolymer of poly (tert-butyl acrylate coacrylic acid) and azobenzene-bearing polymethacrylate, poly (ethylene oxide) (PEO) as the hydrophilic block and a polymethrancrylate spir carries as the hydrophobic block, and combinations thereof.

6. Samenstel van onderdelen volgens een van de voorgaande conclusies, waarbij het vehikel een laag omvat, welke laag is aangepast om ten minste gedeeltelijk te desintegreren of een structurele verandering te ondergaan bij directe of indirecte activering door de fotosensibilisator.The assembly of parts according to any of the preceding claims, wherein the vehicle comprises a layer, which layer is adapted to at least partially disintegrate or undergo a structural change upon direct or indirect activation by the photosensitizer.

7. Samenstel van onderdelen volgens een van de voorgaande conclusies, waarbij de fotosensibilisator ten minste één van een aromatische ring omvat, zoals 1-5 aromatische ringen, een geconjugeerde dubbele binding, een geconjugeerde drievoudige binding, een C=N-binding, een isomere veranderbare C=C cis of transbinding, zoals violantroon, isoviolanthroon, fluoresce-ine, rubreen, 9,10-difenylanthraceen, tetraceen, 13,13'-dibenzantroniel, acrylcarbonylmethyl, nitrtoaryl, coumarine, arylmethyl, en levulinezuur.The assembly of parts according to any of the preceding claims, wherein the photosensitizer comprises at least one of an aromatic ring, such as 1-5 aromatic rings, a conjugated double bond, a conjugated triple bond, a C = N bond, an isomeric changeable C = C cis or transbinding, such as violet throne, isoviol anthracite, fluorescein, rubrene, 9,10-diphenyl anthracene, tetracene, 13,13'-dibenzantrone, acrylic carbonylmethyl, nitrtoaryl, coumarin, arylmethyl, and levulinic acid.

8. Samenstel van onderdelen volgens een der voorgaande conclusies, waarbij de fotosensibilisator een enkelvoudig zuurstof produceert, door een UV-foton splitsbaar is, of een cis-trans-overgang initieert.The assembly of parts according to any of the preceding claims, wherein the photosensitizer produces a single oxygen, is cleavable by a UV photon, or initiates a cis-trans transition.

9. Samenstel van onderdelen volgens een der voorgaande conclusies, waarbij de ten minste ene therapeutische verbinding in een nano-drager is opgenomen.The assembly of parts according to any one of the preceding claims, wherein the at least one therapeutic compound is incorporated in a nano-carrier.

10. Samenstel van onderdelen volgens een van de voorgaande conclusies, waarbij de therapeutische verbinding is gekozen uit ten minste één geneesmiddel, medicijnen, chemotherapeuti-ca, genen, metabolische actieve verbinding (TBC), en antibiotica, of een derivaat daarvan, of een analoog daarvan.The assembly of parts according to any of the preceding claims, wherein the therapeutic compound is selected from at least one drug, drug, chemotherapeutic agent, genes, metabolic active compound (TBC), and antibiotics, or a derivative thereof, or an analogue thereof.

11. Samenstel van onderdelen volgens conclusie 10, waarbij het geneesmiddel is gekozen uit kankermedicijnen en cardioge-neesmiddelen.The assembly of parts according to claim 10, wherein the medicament is selected from cancer drugs and cardiac drugs.

12. Samenstel van onderdelen volgens een der voorgaande conclusies, waarbij het radionuclide fotonen met een maximale intensiteit produceert bij een golflengte van 180-500 nm, zoals 200-360 nm.The assembly of parts according to any one of the preceding claims, wherein the radionuclide produces photons with a maximum intensity at a wavelength of 180-500 nm, such as 200-360 nm.

13. Samenstel van onderdelen volgens een der voorgaande conclusies, waarbij het radionuclide een halfwaardetijd van 5 min-28 dagen heeft.The assembly of parts according to any one of the preceding claims, wherein the radionuclide has a half-life of 5 min-28 days.

14. Samenstel van onderdelen volgens een der voorgaande conclusies, waarbij het radionuclide geconjugeerd is aan het targetingsmiddel, zoals aan een peptide of eiwit.The assembly of parts according to any of the preceding claims, wherein the radionuclide is conjugated to the targeting agent, such as to a peptide or protein.

15. Samenstel van onderdelen volgens een der voorgaande conclusies, waarbij de radionuclidedosis 0,1-200 Gy (J/kg = irn/s^) is.The assembly of parts according to any one of the preceding claims, wherein the radionuclide dose is 0.1-200 Gy (J / kg = irn / s ^).

16. Samenstel van onderdelen volgens een van de conclusies 1-15 voor gebruik in de vervaardiging van een geneesmiddel, zoals een geneesmiddel voor de behandeling van kanker, behandeling van metastasen, zoals diep gelegen metastasen en niet-geidentificeerde metastasen.The assembly of parts according to any of claims 1-15 for use in the manufacture of a medicament, such as a medicament for the treatment of cancer, treatment of metastases, such as deep metastases and unidentified metastases.

17. Geneesmiddel omvattende een samenstel van onderdelen volgens één der conclusies 1-15.A medicament comprising an assembly of parts according to any of claims 1-15.

18. Werkwijze voor het behandelen van een ziekte, omvattende het verschaffen van 0,1-5 ml/kg van een tweede oplossing volgens één van de conclusies 1-15 met het vehikel, het toedienen van 0,1-5 ml/kg van een eerste oplossing volgens een van conclusies 1-14 met radionuclide gekoppeld aan een targetingsmiddel voor een tumorcelontvanger, het koppelen van het targetingsmiddel aan een tumorcelreceptor, en het activeren van het vehikel voor het vrijgeven van de ten minste ene therapeutische verbinding, bij voorkeur met gebruikmaking van getimede opeenvolgende toediening.A method of treating a disease, comprising providing 0.1-5 ml / kg of a second solution according to any one of claims 1-15 with the vehicle, administering 0.1-5 ml / kg of a first solution according to any of claims 1-14 with radionuclide coupled to a tumor cell recipient targeting agent, coupling the targeting agent to a tumor cell receptor, and activating the vehicle to release the at least one therapeutic compound, preferably using of timed consecutive administration.