WO2009107139A1 - Rgd-(bacterio)chlorophyll conjugates for photodynamic therapy and imaging of necrotic tumors - Google Patents
Rgd-(bacterio)chlorophyll conjugates for photodynamic therapy and imaging of necrotic tumors Download PDFInfo
- Publication number
- WO2009107139A1 WO2009107139A1 PCT/IL2009/000228 IL2009000228W WO2009107139A1 WO 2009107139 A1 WO2009107139 A1 WO 2009107139A1 IL 2009000228 W IL2009000228 W IL 2009000228W WO 2009107139 A1 WO2009107139 A1 WO 2009107139A1
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- Prior art keywords
- tumor
- group
- necrotic
- rgd
- compound
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- HISNRBVYBOVKMB-UHFFFAOYSA-N stibonium Chemical compound [SbH4+] HISNRBVYBOVKMB-UHFFFAOYSA-N 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- VTLHPSMQDDEFRU-UHFFFAOYSA-O telluronium Chemical compound [TeH3+] VTLHPSMQDDEFRU-UHFFFAOYSA-O 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000004865 vascular response Effects 0.000 description 1
- 230000007998 vessel formation Effects 0.000 description 1
- 108010047303 von Willebrand Factor Proteins 0.000 description 1
- 102100036537 von Willebrand factor Human genes 0.000 description 1
- 229960001134 von willebrand factor Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0485—Porphyrins, texaphyrins wherein the nitrogen atoms forming the central ring system complex the radioactive metal
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- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
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- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
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- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- A61K51/0446—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A61K51/04—Organic compounds
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- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
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- A61K51/0451—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. phorphine derivatives, bilirubin, biliverdine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
Definitions
- Bchl a bacteriochlorophyll a: pentacyclic 7,8,17,18-tetrahydroporphyrin with a 5 th isocyclic ring, a central Mg atom, a phytyl or geranylgeranyl group at position 17 , a COOCH 3 group at position 13 , an H atom at position 13 , methyl groups at positions 2, 7, 12, 18.
- Bphe bacteriopheophytin a (Bchl in which the central Mg is replaced by two H atoms); Bpheid: bacteriopheophorbide a (the C- 17 2 -free carboxylic acid derived from Bphe without the central metal atom); ChI: chlorophyll; Rhodobacteriochlorin: tetracyclic 7,8, 17, 18-tetrahydroporphyrin having a -CH 2 CH 2 COOH group at position 17, a -COOH at position 13, methyl groups at positions 2, 7, 12, 8, and ethyl groups at positions 3 and 8; Pd-Bpheid: Pd-bacteriopheophorbide a; EC: endothelial cells; ECM: extracellular matrix; NIR: near-infrared; PDT: photodynamic therapy; RGD-4C: the cyclic non-bacteriopheophorbide a; EC: endothelial cells; ECM: extra
- IUPAC numbering of the bacteriochlorophyll derivatives is used throughout the specification. Using this nomenclature, the natural bacteriochlorophylls carry two carboxylic acid esters at positions 13 2 and 17 2 , however they are esterified at positions 13 3 and 17 J . BACKGROUND ART
- necrosis is the result of chronic ischemia that is caused by vascular collapse and rapid tumor cell growth that is higher than the rate of angiogenesis (Leek et al. 1999).
- necrotic areas in solid tumors undergo morphological modifications. At the beginning the original structure is basically preserved, and necrotic cells keep their overall shape but become highly eosinophilic. After some time, this pattern is replaced by liquefaction necrosis, in which the cellular structures are broken down (Leek et al. 1999).
- necrosis was correlated with high vascular density and angiogenesis, high levels of focal macrophage infiltration and decreased patient survival (Kato et al. 1997; Lee et al. 1997; Leek et al. 1999; Tomes et al. 2003).
- Central necrosis which is a common feature of invasive breast cancer, was associated with poor outcome and tumor aggression. Macrophages were shown to be attracted to the necrotic tumors by chemotactic factors, released by hypoxic or dying tumor cells (Leek et al. 1999).
- hypoxia a malignant neoplasm originating from hypoxia.
- hypoxia and anoxia subject the tumor cells to oxidative stress.
- Prolonged hypoxic conditions were shown to increase the rate of mutations, to accelerate the progression of the tumor, to increase angiogenesis and metastatic potential and to activate growth promoting signaling pathways.
- Adaptation to oxidative stress often makes the tumor cells resistant to certain therapeutic modalities (Brown et al., 2001).
- necrosis and hypoxia are very well established, however there might be hypoxic conditions that have not reached necrosis, or necrosis that does not necessarily reflects acute or severe hypoxia (Dewhirst 1998).
- hypoxia induced factor 1 HIFl
- glucose transporter 1 HIF 1
- carbonic anhydrase IX Only detection of all three markers assures the classification of necrosis (Tomes et al. 2003), making the identification of an area as necrotic by gene expression quite complicated.
- hypoxic conditions are known to create a major problem in cancer therapy.
- Hypoxic tumor domains are relatively resistant to radiation treatment since there is a poor promotion of the radiation assault and since stem cells that may eventually be present in the tumor volume do not respond well to the treatment, resulting in tumor re-growth (Brown et al., 1998; Dean et al., 2005).
- chemotherapeutic reagents impose cell death due to interactions with cycling cells, cell arrest because of hypoxia results in resistance to conventional chemotherapy, leaving non-proliferating or slow proliferating cells unharmed (Tannock, 1978).
- hypoxic conditions usually create an acidic environment that might change the nature of the drug, making it less active (Tannock et al., 1989).
- Tumors usually contain irregular and leaky microvessels with heterogeneous blood flow and large intervessel distances. These features, in addition to the absence of proper lymphatic drainage and high interstitial pressures, make diffusion the most important mechanism of extravascular transport of nutrients and drugs in tumors.
- many of the tumor cells are at higher distances from capillaries than cells in the normal tissues, reflected in having insufficient concentrations of antitumor agents at the cell sites.
- the enhanced interstitial fluid pressure due to the lack of lymphatic drainage reduces the convection uptake and further inhibits the distribution of drugs into the tumor cells, particularly that of macromolecules (Minchinton et al, 2006).
- hypoxic tumor domains might help choosing the right treatment - either by improving tumor oxygenation before or during treatment or by using strategies that exploit the hypoxia (Weinmann et al., 2004).
- hypoxia-activated cytotoxins such as 2- cyclopropyl-indoloquinones, AQ4N, Tirapazamine (TPZ) and PR- 104 may help improve the treatment outcome (Brown et al., 2004; Lee et al., 2007; Patterson et al. 2007).
- MRI magnetic resonance imaging
- PET positron emission tomography
- PET positron emission tomography
- Necrosis-avid contrast agents for MRI can be classified into porphyrin-based and non-porphyrin-based agents.
- One of the most known porphyrin-based NACAs is gadophrin-2 that shows specific necrosis accumulation mostly at the margins of the necrotic area. The mechanism of accumulation was suggested to be based on serum albumin (SA) trafficking, but recent studies doubted this approach (Hofmann et al. 1999; Ni et al. 2005)
- the biochemical features that signify blood vessels in tumors may include angiogenesis-related molecules such as certain integrins.
- the integrin family of cell- adhesion receptors comprises distinct 24 ⁇ heterodimers that recognize glycoprotein ligands in the extracellular matrix or on cell surfaces. Many members of the integrin family, including ⁇ 5 ⁇ l, ⁇ l, ⁇ llb ⁇ 3, ⁇ V ⁇ 3, ⁇ V ⁇ 5, ⁇ V ⁇ and ⁇ V ⁇ 8, recognize an Arg-Gly-Asp (RGD) motif within their ligands.
- These ligands include fibronectin, fibrinogen, vitronectin, von Willebrand factor and many other large glycoproteins (Takagi 2004).
- the method enables monitoring cell viability or cell function at a high throughput because of the good signal/noise value (Lyons 2005).
- the main disadvantages of the luciferase/luciferin method are the low anatomic and image resolutions thus requiring a substantial amount of time to collect sufficient photons to form an image from an anesthetized animal.
- increased tissue depth and the need for exogenous delivery of the substrate attenuate the in-vivo light emission (Yang et al., 2000; Lyons, 2005).
- ex-vivo experiments are difficult to perform since ATP is required for the enzyme activity.
- the method involves subjective parameterization that reduces its quantitative value.
- Another way for monitoring tumor progression by optical fluorescence imaging is based on transfecting tumor cells with a stable fluorescent protein such as green fluorescent protein (GFP) and red fluorescent protein (RFP).
- GFP green fluorescent protein
- RFP red fluorescent protein
- the main disadvantages of this method are that (1) the excitation and emission lights are prone to attenuation with increased tissue depth and (2) the autofluorescence of non labeled cells increases noise (Lyons, 2005).
- the main advantages include: multiple reporter wavelengths enabling multiplex imaging; high compatibility with a range of ex-vivo approaches for analytic methods such as fresh tissue analysis; there is no need for preparative procedures for imaging which makes it uniquely suited for visualizing in live tissue; the method is external and noninvasive; the method provides a real-time fluorescence optical imaging of internally growing tumors and metastases in transplanted animals that can give a whole-body image but also the image of single cells extracted from the primary lesion and metastases (Yang et al., 2000; Lyons, 2005). Whole body imaging is one of the most required tools for understanding tumor development. Thus, by genetically labeling of tumor cells with GFP or RPP, external whole body imaging of primary and metastatic tumors can be achieved (Yang et al. 2000).
- Fluorescence tagging is suitable for in-vivo, fresh tissue and in-vitro detection.
- Using tumor cells expressing fluorescent proteins enables the imaging of live animals and the follow up of tumor progression in different time points.
- the RPP has a longer wavelength emission than GFP thus enabling higher sensitivity and resolution of microscopic tumor growth (GFP excitation wavelength - 489nm, emission wave-length - 508nm, RFP excitation wavelength - 558nm, emission wave-length - 583nm).
- Ductal carcinoma in situ comprises a clonal proliferation of cells that appear malignant and accumulate within the lumen of the mammary ducts with no evidence of invasion into the adjacent breast stroma and beyond the epithelial basement membrane.
- DClS lesions There is a significant chance of transforming non-invasive DClS lesions into an invasive, life-threatening disease if it is not treated at an early stage.
- SC breast conserving
- DCIS is a biologically heterogeneous form of malignancy with a diverse clinical presentation, histology, cellular features, and biological potential. It has been classified into comedo (invasive) and non-comedo (non-invasive) carcinomas, where comedo has the higher grade, with a potentially more invasive subtype, characteristically containing a large necrotic area in the ductal lumen and cells with marked cytologic atypia.
- DCIS non-invasive DCIS into an invasive breast tumor may take 15-20 years and involve 14 to 60 percent of the diagnosed women (Burstein et al., 2004).
- DCIS appears to represent a stage of breast cancer development in which many of the molecular events that define invasive breast cancer are already present (Cutuli et al., 2002; Holland et al., 1990). Specifically, -30% of low-grade lesions will develop into invasive carcinoma if left untreated (Sanders et al., 2005). Lesions with a diameter greater than 2.5 cm are frequently accompanied by occult microinvasive tumors that may not exceed 0.1mm. The involvement of tumor margins provides an important prognostic marker.
- Fibrocystic lesions with the highest vascular density are associated with a greater risk of breast cancer (Guidi et al., 1994; Guidi et al., 1997; Guinebretiere et al., 1994). Histopathological examinations of aggressive DCIS lesions were associated with increased MVD and vascular endothelial growth factor (VEGF) expression (Guidi et al., 1997; Schneider et al., 2005). Clinicopathologic correlations also confirm the cardinal role of angiogenesis in the progression of breast cancer, making it attractive target for DCIS therapy and prognosis (Folkman, 1997; Krippl et al., 2003; ReIf et al., 1997).
- VEGF vascular endothelial growth factor
- Vessel cooption growth by intussusception (Patan et al., 1996), vascular mimicry and vasculogenesis are naturally occurring processes that may decrease the tumor's dependence on classical angiogenesis.
- vascular mimicry and vasculogenesis are naturally occurring processes that may decrease the tumor's dependence on classical angiogenesis.
- vasculogenesis Of particular importance is the finding that inflammatory breast cancer depends almost entirely on vasculogenesis, apparently because of the inability of the cancer cells to bind endothelial cells.
- VTP photodynamic therapy
- Dynamic MRI with Gd as a contrast agent is based on enhanced leakiness of the tumor vasculature and currently used for tumor localization in the breast (Rankin, 2000).
- the current use of MRI is limited by the available short integration time of contrast agents that shortly reside but do not selectively taken up by the tumor tissue.
- Photodynamic therapy (PDT) in tumors involves the combination of administered photosensitizer and local light delivery, both innocuous agents by themselves, but in the presence of molecular oxygen they are capable of producing cytotoxic reactive oxygen species (ROS) that can eliminate cells.
- ROS cytotoxic reactive oxygen species
- PDT allows for greater specificity, and has the potential of being more selective yet not less destructive when compared with commonly used chemotherapy or radiotherapy (Dougherty et al. 1998).
- the present invention thus relates to the use of said RGD- bacteriochlorophyll and RGD-chlorophyll conjugates for minimally invasive tumor- targeted imaging, tumor-targeted photodynamic therapy, and/or on-line prognosis of necrotic tumors, and to methods therefore.
- Figs. 2A-2B show fluorescent clones of the transfected cells of Fig. 1 as detected by fluorescence microscope (Nikon, magnification XlO) after 3 sec exposure.
- 2A MDA-MB-231 RFP clone 1 (resistant to G418).
- 2B MDA-MB-231 RFP clone 3 (resistant to hygromycin).
- Figs. 6A-6B show accumulation of compound 13 in MDA-MB-231 -RFP orthotopic tumor (tumor size -0.5 cm 3 ). Mice were injected with compound 13. Images were taken from 20 min to 24 h post drug injection. 6A (top panel): red fluorescence imaging. 6B (bottom panel): NIR fluorescence imaging.
- Figs. 7A-7B show accumulation of compound .13 in MDA-MB-231 -RFP orthotopic tumor (tumor size -0.5 cm 3 ). Mice were injected with compound 13. Images were taken from day 1 to 3 post drug injection. 7A (top panel): red fluorescence imaging. 7B (bottom panel): NIR fluorescence imaging.
- Figs. 9A-9B show accumulation of compound 24 in MDA-MB-231-RFP orthotopic tumor (tumor size ⁇ 1 cm 3 ). Mice were injected with compound 24. Images were taken from 1 h to 24 h post drug injection. 9 A (top panel): red fluorescence imaging. 9B (bottom panel): NIR fluorescence imaging.
- Figs. 11A-11B show accumulation of compound 24 in MDA-MB-231-RFP orthotopic tumor (tumor size -0.5 cm 3 ). Mice were injected with compound 24, and images were taken from 20 min to 24 h post drug injection.
- HA top panel
- HB bottom panel
- Figs. 14A-15B show accumulation of compound 13 in MLS-mBanana orthotopic tumor (tumor size ⁇ 1 cm J ). Mice were injected with compound 13. Images were taken from day 1 to 4 post drug injection. 14A (top panel): red fluorescence imaging. 14B (bottom panel): NIR fluorescence imaging.
- Figs. 15A-15B show accumulation of compound 13 in MLS-mBanana orthotopic tumor (tumor size ⁇ 0.5 cm J ). Mice were injected with compound .13. Images were taken from 10 min to 24 hours post drug injection. 15A (top panel): red fluorescence imaging. 15B (bottom panel): NIR fluorescence imaging.
- Figs. 16A-16B show accumulation of compound 13 in MLS-mBanana orthotopic tumor (tumor size ⁇ 0.5 cm 0 ). Mice were injected with compound 13. Images were taken from day 1 to 4 post drug injection. 16A (top panel): red fluorescence imaging. 16B (bottom panel): NIR fluorescence imaging.
- Figs. 17A-17B demonstrate comparison of compound 13 accumulation in human ovarian MLS-mBanana primary necrotic and non-necrotic tumors. Images were taken 2 days post compound 13_ injection. Images of in-vivo whole-body NIR fluorescence of compound 13 were taken. 17A: Non-necrotic tumors (-0.5 cm J ). 17B: Necrotic tumors (-1 cm J ).
- Figs. 21A-21B show accumulation of compound 25 in MDA-MB-231-RFP orthotopic non-necrotic tumor (tumor size -0.5 cm 3 ). Mice were injected with compound 25, and images were taken from day 1 to 3 post drug injection. 21A (top panel): red fluorescence imaging. 21B (bottom panel): NIR fluorescence imaging.
- Figs. 22A-22D show competition assay of compound 13 accumulation in orthotopic human breast MDA-MB-231-RFP primary tumor (tumor size -0.5 cm 3 ) when administrated 1 h after free c(RGDfK) administration. Images were taken 24 hours post compound 13 administration. 22A, 22B - red fluorescence imaging; 22C, 22D - NIR fluorescence imaging. 22 A, 22C: compound 13 was administrated Ih after free c(RGDfK) administration (competition). 22B, 22D: control, only compound 13 was administrated.
- Figs. 23A-23F show accumulation of compound 13 in the viable versus necrotic areas of the MDA-MB-231-RFP orthotopic tumor measured 10 min post drug injection.
- Figs. 27A-27F show accumulation of compound 13 in the viable versus necrotic areas of the MDA-MB-231-RFP orthotopic tumor measured 3 days after drug injection.
- Figs. 27A, 27B, 27C (top panel) and 27D, 27E, 27F (bottom panel) are as described above for Figs. 23A, 23B, 23C and 23D, 23E, 23F, respectively.
- Figs. 28A-28F show accumulation of compound 13 in the viable versus necrotic areas of the MD A-MB -231 -RFP orthotopic tumor measured 5 days after drug injection.
- Figs. 28A, 28B, 28C (top panel) and 28D, 28E, 28F (bottom panel) are as described above for Figs. 23A, 23B, 23C and 23D, 23E, 23F, respectively.
- Figs. 32A-32F show accumulation of compound 13 in non-central necrosis of MLS-mBanana tumo, measured 7 days post drug injection.
- Figs. 3OA, 3OB, 3OC (top panel) and 3OD, 3OE, 3OF (bottom panel) are as described above for Figs. 23A, 23B, 23C and 23D, 23E, 23F, respectively.
- RGD peptidomimetic refers to compounds, particularly, non-peptidic compounds, that mimic peptides and have the RGD motif.
- RGD peptides are known to interact with integrin receptors of cells and have the potential to initiate cell-signaling processes and influence many diseases, for these reasons, the integrin RGD bonding site has been considered an attractive pharmaceutical target.
- amino acid includes the 20 naturally occurring amino acids as well as non-natural amino acids.
- natural amino acids suitable for the invention include, but are not limited to, Ala, Arg, Asp, Asn, Cys, His, GIn, GIu, GIy, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and VaI.
- D-modifications of amino acids and N-alkylation of the peptide bond are most beneficial to prevent peptide cleavage by enzymes in the organism.
- a D-amino acid is indicated by a small letter as for the D-phenylalanine 'f residue in the peptide cycloRGDfK of SEQ ID NO: 1 used herein.
- the peptide is the cyclic pentapeptide
- the photosensitizer is conjugated to a RGd peptidomimetic.
- the RGD peptidomimetic is a non-peptidic compound comprising a guanidine and a carboxyl terminal groups spaced by a chain of 1 1 atoms, at least 5 of said atoms being carbon atoms, and said chain comprises one or more O, S or N atoms and may optionally be substituted by oxo, thioxo, halogen, amino, C1-C6 alkyl, hydroxyl, or carboxy or one or more atoms of said chain may form a 3-6 membered carbocyclic or heterocyclic ring.
- the RGD peptidomimetic above comprises in the chain N atoms and is substituted by an oxo group.
- the RGD peptidomimetic has the formula:
- X is O or N-R 7 ;
- R 1 , R' 2 and R 6 each independently is Y-R 8 , -NR 9 R' 9 or -N + R 9 R' 9 R" 9 A " or R 1 and R 6 in formula II together with the carbon atoms to which they are attached form a ring comprising an RGD peptide or RGD peptidomimetic; Y is O or S;
- R 7 , Rg, R 9] R' 9 and R" 9 each independently is: (a) H; (b) C
- CpC 25 hydrocarbyl preferably C 1 -C 25 alkyl, more preferably CpC 10 or CpC 6 alkyl, containing one or more heteroatoms and/or one or more carbocyclic or heterocyclic moieties;
- CpC 25 hydrocarbyl preferably CpC 25 alkyl, more preferably CpCi 0 or
- CpC 25 hydrocarbyl preferably CpC 25 alkyl, more preferably CpCio , or CpC 6 alkyl substituted by a residue of an amino acid, a peptide, preferably an RGD peptide, a protein, a monosaccharide, an oligosaccharide, a polysaccharide, or a polydentate ligand and its chelating complex with metals; or
- carbocyclic moiety refers to a monocyclic or polycyclic compound containing only carbon atoms in the ring(s).
- the carbocyclic moiety may be saturated, i.e. cycloalkyl, or unsaturated, i.e. cycloalkenyl, or aromatic, i.e. aryl.
- aryl or “heteroaryl” may be substituted by one or more radicals such as halogen, C 6 -C 14 aryl, C 1 -C 25 alkyl, nitro, OR, SR, -COR, -COOR, -
- R, R' and R" may each independently be H or hydrocarbyl or heterocyclyl, or R' and R' ' together with the N atom to which they are attached form a 3-7 membered saturated ring, as defined herein.
- R is H
- R' and R" each is C r C 6 alkyl such as methyl, ethyl, propyl, butyl, hexyl.
- R and R' may each independently be H or hydrocarbyl. preferably CpC 6 alkyl. or heterocyclyl, or R and R' together with the N atom to which they are attached form a 3-7 membered saturated ring, as defined herein.
- the chlorophyll or bacteriochlorophyll derivative contains a cyclic ammonium group of the formula -N + (RR 5 R"), wherein two of R, R' and R" together with the N atom form a 3-7 membered saturated ring defined hereinbelow.
- a 3-7 membered saturated ring formed by two of R, R' and R" together with the N atom to which they are attached may be a ring containing only N such as aziridine, pyrrolidine, piperidine, piperazine or azepine, or it may contain a further heteroatom selected from O and S such as morpholine or thiomorpholine.
- the further N atom in the piperazine ring may be optionally substituted by alkyl, e.g. Ci-C 6 alkyl, that may be substituted by halo, OH or amino.
- the onium groups derived from said saturated rings include aziridinium. pyrrolidinium, piperidinium, piperazinium, morpholinium, thiomorpholinium and azepinium.
- a cation derived from a N-containing heteroaromatic radical denotes a cation derived from a N-heteroaromatic compound that may be a mono- or polycyclic compound optionally containing O, S or additional N atoms.
- the ring from which the cation is derived should contain at least one N atom and be aromatic, but the other ring(s), if any, can be partially saturated.
- the positively charged group may also be an onium group not containing nitrogen such as but not limited to, phosphonium [-P + (RR 5 R")], arsonium [- As + (RR 5 R")], oxonium [-O + (RR 5 )], sulfonium [-S + (RR 5 )], selenonium [-Se + (RR')], telluronium [-Te + (RR 5 )], stibonium [-Sb + (RR 5 R")], or bismuthonium [- Bi + (RR 5 R")] group, wherein each of R, R 5 and R", independently, is H, hydrocarbyl or heterocyclyl, preferably C r C 6 alkyl such as methyl, ethyl, propyl, butyl, pentyl or hexyl, or aryl, preferably, phenyl.
- R, R 5 and R independently, is H, hydrocarbyl or heterocyclyl, preferably C r C 6 alky
- the 3-7 membered saturated ring may be aziridine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine or piperazine optionally substituted at the additional N atom by C 1 -C 6 alkyl optionally substituted by halo, hydroxyl or amino, and the N-containing heteroaromatic radical may be pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, quinolinyl, isoquinolinyl, pyrimidyl, 1 ,2,4-triazinyl, 1,3,5- triazinyl or purinyl.
- the photosensitizer is a bacteriochlorophyll of formula II and R 6 is -NH-(CH 2 ) 3 -NH-(CH 2 ) 3 -NH 2 , -NH-(CH 2 ) 2 -l-morpholino, or - NH-(CH 2 ) 3 -piperazino-(CH 2 ) 3 -NH 2 .
- the conjugate comprises
- M is 2H, Ri, R' 2 , R 4 , R' 4 and R 6 are as defined above and P is a linear peptide selected from GRGDSP of SEQ ID NO: 6, or GRGDSPK of SEQ ID NO: 7 or (GRGDSP) 4 of SEQ ID NO: 8, most preferably
- the conjugate comprises a ChI of the formula II wherein M is selected from Mn, Cu or 2H; Ri is NH-P, wherein P is the residue of an RGD-containing peptide or RGD peptidomimetic linked directly to the NH- or via a spacer; R 4 at position 3 is vinyl and at position 8 is ethyl; R' 4 is methyl; and R 6 is -NH-(CH 2 ) 2 -SO 3 " Me + , wherein Me + is Na + or K + .
- M is 2H or Cu or Mn
- R 4 , R' 4 and R 6 are as defined above and the photosensitizer is conjugated to the pentacyclic RGD-containing peptide c(RGDfK) of SEQ ID NO: 1.
- the method is used for treatment of localized breast cancer, particularly ductal carcinoma in situ.
- a method for tumor photodynamic therapy of necrotic tumors comprises: (a) administering to an individual in need a RGD peptide-photosensitizer conjugate according to the invention; and (b) irradiating the local of the tumor and its necrotic domains after determining the presence of necrotic domains at least 24 hours, preferably 2, 3, 4, 5, 6, 7 or 8 days after injection of the conjugate, by any of the methods described herein.
- the histology of large and small tumors from animals treated with compound 13 appears to support the suggested accumulation pattern and provide some clues to the underlying mechanism. There is a very good overlap between the viable tumor domain and compound 13 fluorescence in the first few hours, and a very good overlap between the fluorescence of 13 and the necrotic domains at 24 h and longer times post administration.
- EPR enhanced permeability and retention
- the possible targeting and prolonged retention of fluorescence Chls/Bchls in the necrotic domain may enable their early detection and help predicting tumor prognosis and modes of treatment. Moreover, it opens the way for the delivery of hypoxia triggered drugs.
- Main filter set for tumor imaging comprised excitation filter at 500-550 nm and emission filter at 575-650 nm; Background filter set for subtracting tissue auto- fluorescence comprised excitation filter at 460-490 nm and emission filter at 575-650 nm.
- Drugs imaging main filter set comprised excitation filter at 665-695 nm and emission filter at 810-875 nm. Images were obtained during the same exposure time and are illustrated on the same linear color scale to allow for a qualitative comparison.
- Example 8 Uptake of compound 13 in MLS-mBanana primary necrotic tumors implanted in the mouse mammary pad
- the compound 13 concentration in the necrotic tumors appears to be much higher than that in the non-necrotic ones as shown in Figs. 17A-17B. Peak tumor fluorescence (fluorescence average measurements from 4 animals) was detected at 1- 3.5 h post drug injection.
- Figs. 33A-33D show histological sections of the tumor viable and necrotic domains of tumor excised 4 hours after drug injection. These observations should complement the RFP and compound 13 tissue distribution imaging previously obtained. As seen in Fig. 33A, the balk of the mass is composed of opaque, tan and necrotic tissue. From Fig. 33B, a correlation between the macroscopic and microscopic features can be noted.
- This experiment aims at quantifying the course of drug spread and accumulation in various organs of the body, and demonstrating in an un-biased way that the drug indeed accumulates eventually in the tumor.
- Anaesthetized mice bearing MDA-MB-231-RFP tumors are injected i.v. with compound 13, 15 mg/kg. Mice are sacrificed at several time points after injection. Tissues (blood, kidneys, liver, skin, fat, muscle, spleen, intestine, brain, heart, lungs and tumor) are collected into pre-weighted vials and frozen. Tissue samples are homogenized and the drug is extracted in methanol ( ⁇ 1 ml methanol per 100 mg tissue). Samples are then analyzed for drug content by fluorescent analysis.
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Abstract
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Priority Applications (13)
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JP2010548248A JP5620279B2 (en) | 2008-02-27 | 2009-03-01 | RGD- (bacterio) chlorophyll conjugate for photodynamic treatment and imaging of necrotic tumors |
US12/920,088 US8815213B2 (en) | 2008-02-27 | 2009-03-01 | RGD-(bacterio)chlorophyll conjugates for photodynamic therapy and Imaging of Necrotic tumors |
MX2010009530A MX2010009530A (en) | 2008-02-27 | 2009-03-01 | Rgd-(bacterio)chlorophyll conjugates for photodynamic therapy and imaging of necrotic tumors. |
AU2009219682A AU2009219682B2 (en) | 2008-02-27 | 2009-03-01 | RGD-(bacterio)chlorophyll conjugates for photodynamic therapy and imaging of necrotic tumors |
CN200980115901.2A CN102036684B (en) | 2008-02-27 | 2009-03-01 | For RGD (bacterium) chlorophyll conjugate that PDT and necrotic tumor are imaged |
ES09714191T ES2764781T3 (en) | 2008-02-27 | 2009-03-01 | RGD- (bacterio) chlorophyll conjugates for use in the diagnosis of tumors comprising necrotic domains |
CA2717060A CA2717060C (en) | 2008-02-27 | 2009-03-01 | Rgd-(bacterio)chlorophyll conjugates for photodynamic therapy and imaging of necrotic tumors |
RU2010139461/15A RU2518296C2 (en) | 2008-02-27 | 2009-03-01 | Rgd-(bacterio)chlorophyll conjugates for photodynamic therapy and necrotic tumour imaging |
EP09714191.5A EP2257309B1 (en) | 2008-02-27 | 2009-03-01 | Rgd-(bacterio)chlorophyll conjugates for use in diagnosis of tumors comprising necrotic domains |
DK09714191.5T DK2257309T3 (en) | 2008-02-27 | 2009-03-01 | RGD (BACTERY) CHLOROPHYL CONJUGATES USED FOR THE DIAGNOSIS OF TUMORS CONTAINING NECROTIC DOMAINS |
BRPI0907791-0A BRPI0907791A2 (en) | 2008-02-27 | 2009-03-01 | Rgd- (bacterio) chlorophyll conjugates for photodynamic therapy and imaging of necrotic tumors |
IL207795A IL207795A (en) | 2008-02-27 | 2010-08-25 | Rgd-(bacterio)chlorophyll conjugates for use in photodynamic therapy and imaging of necrotic tumors |
ZA2010/06789A ZA201006789B (en) | 2008-02-27 | 2010-09-22 | Rgd-(bacterio)chlorophyll conjugates for photodynamic therapy and imaging of necrotic tumors |
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US (1) | US8815213B2 (en) |
EP (2) | EP2712627A3 (en) |
JP (1) | JP5620279B2 (en) |
KR (1) | KR101595138B1 (en) |
CN (1) | CN102036684B (en) |
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ES (1) | ES2764781T3 (en) |
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US10933134B2 (en) | 2017-03-16 | 2021-03-02 | Memorial Sloan Kettering Cancer Center | Combination therapies for treatment of cancer |
US11364297B2 (en) | 2010-07-09 | 2022-06-21 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Photosensitizing antibody-fluorophore conjugates |
US11781955B2 (en) | 2014-08-08 | 2023-10-10 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Photo-controlled removal of targets in vitro and in vivo |
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ES2764781T3 (en) | 2020-06-04 |
DK2257309T3 (en) | 2020-01-20 |
MX2010009530A (en) | 2010-11-30 |
JP5620279B2 (en) | 2014-11-05 |
CN102036684A (en) | 2011-04-27 |
EP2712627A2 (en) | 2014-04-02 |
EP2257309B1 (en) | 2019-10-16 |
KR20100127798A (en) | 2010-12-06 |
CA2717060C (en) | 2016-11-01 |
AU2009219682A1 (en) | 2009-09-03 |
CA2717060A1 (en) | 2009-09-03 |
EP2257309A1 (en) | 2010-12-08 |
BRPI0907791A2 (en) | 2015-08-04 |
KR101595138B1 (en) | 2016-02-18 |
RU2010139461A (en) | 2012-04-10 |
PT2257309T (en) | 2020-01-22 |
US20110064658A1 (en) | 2011-03-17 |
CN102036684B (en) | 2017-06-09 |
ZA201006789B (en) | 2012-01-25 |
RU2518296C2 (en) | 2014-06-10 |
AU2009219682B2 (en) | 2015-06-18 |
JP2011513298A (en) | 2011-04-28 |
EP2712627A3 (en) | 2014-04-16 |
US8815213B2 (en) | 2014-08-26 |
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