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(12) Patent Application Publication (10) Pub. No.: US 2011/0104074 A1 Kakar (43) Pub US 2011 0104074A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0104074 A1 Kakar (43) Pub. Date: May 5, 2011 (54) METHODS FORTARGETED CANCER Publication Classification TREATMENT AND DETECTION (51) Int. Cl. A61R 49/18 (2006.01) (75) Inventor: Sham S. Kakar, Prospect, KY (US) A638/22 (2006.01) (73) Assignee: UNIVERSITY OF LOUISVILLE 3. Wi. C RESEARCH FOUNDATION, (2006.01) INC., Louisville, KY (US) (52) U.S. Cl. ........... 424/9.32: 514/9.7: 424/450; 424/9.1 (21) Appl. No.: 12/999.404 (57) ABSTRACT 1-1. A method for treating a cancer is provided that comprises (22) PCT Filed: Jun. 18, 2009 identifying a subject in need of treatment for a cancer and administering to the Subject a composition that is comprised (86). PCT No.: PCT/USO9/47816 of a plurality of a ligand for a luteinizing hormone-releasing S371 (c)(1) hormone receptor and a plurality of a chemotherapeutic (2), (4) Date: Dec. 16, 2010 agent, where each ligand and each chemotherapeutic agent s e - V.9 are conjugated to a nanoparticle. Further provided are meth O O ods for detecting a cancer in a Subject that comprise admin Related U.S. Application Data istering to a subject an imaging agent comprised of a plurality (60) Provisional application No. 61/073,635, filed on Jun. of a ligand for a luteinizing hormone-releasing hormone 18, 2008. receptor conjugated to a nanoparticle. Patent Application Publication May 5, 2011 Sheet 1 of 13 US 2011/O104074 A1 - LHRH 8x8. DOX FIG. 1 Patent Application Publication May 5, 2011 Sheet 2 of 13 US 2011/O104074 A1 HH: HRH-N-3 S A S 6 3: S C ; 2. Concentration (nM) FIG. 2 Patent Application Publication May 5, 2011 Sheet 3 of 13 US 2011/O104074 A1 24h s FIG. 3A S %· : Six-SLSH38 AFSS $8: FIG. 3B Patent Application Publication May 5, 2011 Sheet 4 of 13 US 2011/O104074 A1 ##########3% - - Ss FIG. 3C Patent Application Publication May 5, 2011 Sheet 5 of 13 US 2011/O104074 A1 : s: - s: s - HRH FIG. 4A 8 ? s 23: Essix-S-E HS Saif S&S FIG. 4B Patent Application Publication May 5, 2011 Sheet 6 of 13 US 2011/O104074 A1 %É FIG. 4C Patent Application Publication May 5, 2011 Sheet 7 of 13 US 2011/O104074 A1 #############|?% S. $ 3-is: FIGSA %;? F8 i33. FIG.SB Patent Application Publication May 5, 2011 Sheet 8 of 13 US 2011/O104074 A1 %4)); SS-SSF 33: FE: FIG SC Patent Application Publication May 5, 2011 Sheet 9 of 13 US 2011/O104074 A1 .5 - - ,4- 0.035 - s 0.03 - a .25 - is , - S. 0.015 - l - .5 - 2 4. 24 2. 4. 2A 2. 4. 24h Ox NP LHRHNP-DOX FIG. 6 Patent Application Publication May 5, 2011 Sheet 10 of 13 US 2011/O104074 A1 Control FNP OX-FMP HRH-FNOX FIG 7 Patent Application Publication May 5, 2011 Sheet 11 of 13 US 2011/O104074 A1 3500 3000 2500 1500 1000 f e e 9 || 9 || 9 || 9 || 9, e e s es e e e e e s e es s s vs is s s s s s s s o o o o s er o c to o d r o C er s ey s o N N n N | N | N | N n n N N N N N N n N n N Group 1 (PBS) Group 2 (Free Group 3 (Dox- Group 4 (Dox Group 5 (Alexa Dox) Dox-NP) FIG. 8 Patent Application Publication May 5, 2011 Sheet 12 of 13 US 2011/O104074 A1 C2 - O. 8 - 0. 5 - O. 4 - O. 2 - ),3 - , 6 - ), A - 0.02 - Jouan)º’s Áreao ÁæAo Áreao Dox FIG. 9 Patent Application Publication May 5, 2011 Sheet 13 of 13 US 2011/O104074 A1 ySOSome titochotifia Nicetis FIG. 10A DCX-FMP-L-R FNR Y FC were mates lysosome Mitochondria Nicies FG, 10B US 2011/O 104074 A1 May 5, 2011 METHODS FORTARGETED CANCER known treatment methods for certain cancers sufficiently TREATMENT AND DETECTION address the administration of a more potent and more specific drug for the treatment of a cancer, which exhibits minimal or RELATED APPLICATIONS no cytotoxicity to normal cells or tissues. 0001. This application claims priority from U.S. Provi sional Application Ser. No. 61/073,635, filed Jun. 18, 2008, SUMMARY the entire disclosure of which is incorporated herein by this 0007. This Summary describes several embodiments of reference. the presently-disclosed subject matter, and in many cases lists variations and permutations of these embodiments. This GOVERNMENT INTEREST Summary is merely exemplary of the numerous and varied 0002. Subject matter described herein was made with U.S. embodiments. Mention of one or more representative features Government support under Grant Number W81XWH-06 of a given embodiment is likewise exemplary. Such an awarded by the Department of Defense. The government has embodiment can typically exist with or without the feature(s) certain rights in the described subject matter. mentioned; likewise, those features can be applied to other embodiments of the presently-disclosed subject matter, TECHNICAL FIELD whether listed in this Summary or not. To avoid excessive repetition, this Summary does not list or Suggest all possible 0003. The presently-disclosed subject matter relates to combinations of such features. methods for targeted cancer treatment and detection. In par 0008. In some embodiments of the presently-disclosed ticular, the presently-disclosed subject matter relates to meth Subject matter, a method for treating a cancer in a subject is ods for targeted cancer treatment that make use of a nanopar provided. In some embodiments, the method comprises iden ticle conjugated with a plurality of ligands for a luteinizing tifying a subject in need of a treatment for a cancer and hormone-releasing hormone receptor and a plurality of a administering to the Subject an effective amount of a compo chemotherapeutic agent, and methods for targeted cancer sition that is comprised of a plurality of a chemotherapeutic detection that make use of a nanoparticle conjugated with a agent and a plurality of a ligand for a luteinizing hormone plurality of ligands for a luteinizing hormone-releasing hor releasing hormone (LHRH) receptor, where both the ligand mone receptor. for the LHRH receptor and the chemotherapeutic agent are conjugated to a nanoparticle. In some embodiments, the com BACKGROUND position is PEGylated. 0004. Despite the progress that has been made in the treat 0009. In some embodiments of the presently-disclosed ment and diagnosis of various cancers, cancer continues to be methods, the ligand for an LHRH receptor comprises LHRH a significant health problem in the United States and other oran analog thereof. In some embodiments, the ligand can be developed countries with one in four deaths currently being D-Trp. LHRH. In some embodiments, the plurality of the attributed to cancer. For example, ovarian cancer is the lead ligand for an LHRH receptor comprises about 150 to about ing cause of gynecological malignancy and, in 2008, approxi 250 molecules of the ligand. In some embodiments, about mately 21,650 new cases of ovarian cancer and 15.520 deaths 200 molecules of the ligand for an LHRH receptor can be were expected in the United States alone (8). Indeed, the cure conjugated to a nanoparticle. rate for ovarian cancer diagnosed at an advanced stage is less 0010. In some embodiments of the presently-disclosed than 20% due the absence of symptoms in the early stage of therapeutic methods, the plurality of chemotherapeutic the disease. Unlike colon and cervical cancers, ovarian cancer agents, which are conjugated to the nanoparticle, comprises has no identifiable precancerous lesions that can be used for about 50 to about 100 molecules of the chemotherapeutic screening. In fact, Screening by transvaginal ultrasonography agent. In some embodiments, the plurality of the chemothera and radioimmunoassay for CA-125 show low specificity and peutic agent comprises about 75 molecules of the chemo sensitivity, which make these two methods unreliable for therapeutic agent. In some embodiments, the chemotherapeu detecting the initial stages of disease. tic agent is cisplatin, carboplatin, paclitaxel, topotecan, or 0005. Currently, the primary treatment modality for ova doxorubicin. In some embodiments, the concentration of the rian cancer is cytoreductive Surgery followed by adjuvant chemotherapeutic agent that is delivered to a Subject via the chemotherapy, radiotherapy, or both (9,10). While this strat presently-disclosed therapeutic methods, is about 5ug/kg to egy has been Successfully employed in a number of patients, about 15 ug/kg. In some embodiments, the concentration of it is always accompanied by cytotoxicity to normal cells and the chemotherapeutic agent is about 9.6 g/kg. tissues, and multidrug resistance (MDR). For ovarian cancer 0011. In some embodiments, the nanoparticle, which is treatment, a number of drugs including cisplatin cis-dichlo conjugated to the plurality of ligands for an LHRH receptor rodiamine platinum (CDDP), carboplatin, oxaliplatin, pacli and the plurality of chemotherapeutic agents, is a gold nano taxel, topotecan, and DOXILR) are clinically used. These particle or a liposome. In some embodiments, the nanopar drugs are typically effective in Suppressing ovarian tumors; ticle is a pure gold nanoparticle. Further, in Some embodi however, due to the high doses of each drug that are admin ments, the nanoparticle is a pure gold nanoparticle, which is istered to a patient, and which are required to achieve effec conjugated to about 200 molecules of a D-Trp. luteinizing tive tumor cell death, almost every drug presently used is hormone-releasing hormone and to about 75 molecules of accompanied by cytotoxicity to normal cells and tissues.
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