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EP-3911336-B1 - PSMA LIGAND TARGETED COMPOUNDS AND USES THEREOF

EP3911336B1EP 3911336 B1EP3911336 B1EP 3911336B1EP-3911336-B1

Inventors

  • BASILION, JAMES
  • BURDA, CLEMENS
  • LUO, Dong
  • WANG, XINNING

Dates

Publication Date
20260506
Application Date
20200121

Claims (10)

  1. A composition for detecting and/or treating cancer, the composition comprising a plurality of compounds that include formula (I): wherein: n and n 1 are each independently 1, 2, 3, or 4; L is an optionally substituted aliphatic or heteroaliphatic linking group; B comprises at least one negatively charged amino acid; and Z has the formula wherein Z is directly or indirectly linked to B, wherein the plurality of compounds including formula (I) form gold nanoclusters.
  2. The composition of claim 1 for detecting and/or treating cancer, wherein B has the following formula: wherein m is 1, 2, 3, or 4, X 1 is an amino acid, and wherein Z is directly or indirectly linked to X 1 .
  3. The composition of claim 1 for detecting and/or treating cancer, wherein B has the following formula: wherein m is 1, 2, 3, or 4.
  4. The composition of claim 1 for detecting and/or treating cancer, wherein L includes at least one ring selected from the group consisting of an optionally substituted 4 to 7 membered nonaromatic heterocyclic ring and an optionally substituted C4-C7 cycloalkyl ring.
  5. The composition of claim 1 for detecting and/or treating cancer, comprising a compound of the formula (II): wherein m, n, and n 1 are each independently 1, 2, 3, or 4, wherein m 1 is 3-7, and wherein the plurality of compounds according to formula (II) form gold nanoclusters.
  6. The composition of claims 1 to 5 for detecting and/or treating cancer, wherein the gold nanoclusters include 10-150 gold atoms, or preferably 10-40 gold atoms.
  7. The composition of claims 1 to 5 for detecting and/or treating cancer, wherein the gold nanoclusters are less than 10 nm in diameter, preferably, less than 5 nm in diameter.
  8. The composition of claims 1 to 5 for detecting and/or treating cancer, wherein the cancer is a PSMA expressing cancer selected from glioma, retinoblastoma, lung cancer, melanoma, breast cancer, ovarian cancer, endometrial cancer, and prostate cancer, preferably, prostate cancer.
  9. The composition of claims 1 to 5 for detecting and/or treating cancer, wherein gold nanoclusters are detectable in a subject by at least one positron emission tomography (PET) imaging or computer tomography (CT) imaging.
  10. The composition of claims 1 to 5 for detecting and/or treating cancer, being formulated for intravenous injection.

Description

RELATED APPLICATION This application claims priority from U.S. Provisional Application No. 62/794,251, filed January 18, 2019. TECHNICAL FIELD This application relates to prostate-specific membrane antigen (PSMA) ligand targeted gold compounds, nanocluster aggregates thereof and to their use in compositions for targeting, imaging, and treating cancer. BACKGROUND Prostate cancer is the most diagnosed cancer among men in the United States. For treatment of prostate cancer, radical prostatectomies still remains the most direct and effective approach, however, when cancer has extended outside the prostate, surgery may be unable to remove all the malignant nodules, resulting in a high recurrence rate of cancer. In this case, radiation therapy, for instance, is necessary to reduce surgery-related morbidities. More than half of the patients receive radiation in the form of electrons, protons or photons (gamma- or X-rays) during their battle against cancers. However, in the practice of radiation treatment, normal tissues are also exposed and potential impairment is unavoidable. Even given recent advances, radiotherapy can still be hardly used alone for tumor eradication, especially when the tumor cells are radioresistant (e.g., hypoxic), underirradiated, or outside the targeted region. Prostate-specific membrane antigen (PSMA) is a 120 kDa protein expressed in prostate tissues and was originally identified by reactivity with a monoclonal antibody designated 7E11-C5 (Horoszewicz et al., 1987, Anticancer Res. 7:927-935; U.S. Pat. No. 5,162,504). PSMA is characterized as a type II transmembrane protein sharing sequence identity with the transferrin receptor (Israeli et al., 1994, Cancer Res. 54:1807-1811). PSMA is a glutamate carboxy-peptidase that cleaves terminal carboxy glutamates from both the neuronal dipeptide N-acetylaspartylglutamate (NAAG) and gamma-linked folate polyglutamate. That is, expression of PSMA cDNA confers the activity of N-acetylated α-linked acidic dipeptidase or "NAALADase" activity (Carter et al., 1996, PNAS 93:749-753). PSMA is expressed in increased amounts in prostate cancer, and elevated levels of PSMA are also detectable in the sera of these patients (Horoszewicz et al., 1987, supra; Rochon et al., 1994, Prostate 25:219-223; Murphy et al., 1995, Prostate 26:164-168; and Murphy et al., 1995, Anticancer Res. 15:1473-1479). As a prostate carcinoma marker, PSMA is believed to serve as a target for imaging and cytotoxic treatment modalities for prostate cancer. Prostate carcinogenesis, for example, is associated with an elevation in PSMA abundance and enzymatic activity of PSMA. PSMA antibodies, particularly indium-111 labeled and tritium labeled PSMA antibodies, have been described and examined clinically for the diagnosis and treatment of prostate cancer. PSMA is expressed in prostatic ductal epithelium and is present in seminal plasma, prostatic fluid and urine. Recent evidence suggests that PSMA is also expressed in tumor associated neovasculature of a wide spectrum of malignant neoplasms including conventional (clear cell) renal carcinoma, transitional cell carcinoma of the urinary bladder, testicular embryonal carcinoma, colonic adenocarcinoma, neuroendocrine carcinoma, gliobastoma multiforme, malignant melanoma, pancreatic ductal carcinoma, non-small cell lung carcinoma, soft tissue carcinoma, breast carcinoma, and prostatic adenocarcinoma. (Chang et al. (1999) Cancer Res. 59, 3192-3198). Gold has excellent radiation enhancing capability as it exhibits great mass energy absorption coefficients. Gold has also been shown to generate secondary radiation and emit high energy in the form of scattered photons, photoelectrons, Compton electrons, auger electrons, electro-positron pairs and fluorescence photons upon radiation, and induce free radicals and ionizations to kill cancer cells. In the development of gold nanoparticle-based radiosensitizers, high tumor targeting and fast body clearance is the key, as an unnecessary over-exposure of radiation to healthy tissue and potential gold particle-induced toxicity are not desirable. There remains a need for an ideal radiosensitizer developed for cancer, such a prostate cancer. WO 2014/127365 A1 describes PSMA ligands and uses thereof. SUMMARY The invention is set out in the appended claims. Other embodiments described herein relate to a composition for use in detecting and/or treating cancer, such as prostate cancer, in a subject. The composition can include a plurality of compounds that include the formula (I): wherein: n and n1 are each independently 1, 2, 3, or 4;L is an optionally substituted aliphatic or heteroaliphatic linking group;B comprises at least one negatively charged amino acid; and Z has the formula wherein Z is directly or indirectly linked to B, wherein the plurality of compounds including formula (I) form gold nanoclusters. In some embodiments, L can include at least one ring selected from the group consisting of an optionall