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Tumor-targeted nanodelivery systems to improve early MRI detection of cancer

a nano-targeted, cancer-targeted technology, applied in the field of drug delivery, cancer treatment and diagnosis, pharmaceuticals, etc., can solve the problems of glucose uptake, significant limitations of current contrast media, mainly based on glucose uptak

Inactive Publication Date: 2014-06-26
GEORGETOWN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides methods for preparing and using cationic immunoliposome complexes for imaging and treating cancer. These complexes consist of a cationic liposome, an antibody or antibody fragment, and an imaging agent or anti-cancer agent. The antibody or antibody fragment is not chemically conjugated to the cationic liposome. The complexes can be administered to a patient through various routes, such as intravenous, intramuscular, or intradermal injection. The technical effects of this invention include improved imaging and treatment of cancer with improved targeting and reduced toxicity.

Problems solved by technology

While free gadolinium is highly toxic, and thus unsuitable for clinical use, chelation with diethylenetriamine pentacetic acid (DTPA) generates a well tolerated, stable, strongly paramagnetic complex.
However, there are significant limitations with current contrast media, including that they are mainly based on perfusion and diffusion labels, and glucose uptake.
Thus, tumors are not specifically targeted by these contrast agents.
In addition, active benign processes cannot always be separated from malignant, e.g. benign enhancing areas on breast MRI, chronic pancreatitis vs pancreatic carcinoma.
There is also insufficient uptake by small tumors of these agents, and thus poor sensitivity and lack of early detection which is particularly critical in diseases like lung cancer.
It may not be possible to detect solitary pulmonary nodules or pleural nodules.

Method used

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  • Tumor-targeted nanodelivery systems to improve early MRI detection of cancer
  • Tumor-targeted nanodelivery systems to improve early MRI detection of cancer
  • Tumor-targeted nanodelivery systems to improve early MRI detection of cancer

Examples

Experimental program
Comparison scheme
Effect test

example 1

Immunoliposome Complexes Comprising Magnevist®

Materials and Methods:

[0074]Cell Lines

[0075]Human lymphoblastic leukemia cell line K562 was obtained from the Lombardi Comprehensive Cancer Center Tissue Culture core facility. These suspension cells were maintained in RPMII640 supplemented with 10% Heat Inactivated FBS plus 2 mM L-Glutamine, and 50 μg / ml each of penicillin, streptomycin and neomycin. Human pancreatic cancer cell line CaPan-1 (obtained from the American Type Culture Collection (ATCC), 10801 University Boulevard, Manassas, Va. 20110-2209) was derived from a metastatic adenocarcinoma of the pancreas. It was maintained in Iscov's Modified Dulbecco's Medium containing 4 mM L-Glutamine and Sodium Bicarbonate, supplemental with 20% non-Heat Inactivated FBS, 2 mM L-Glutamine and 50 μg / mL each of penicillin, streptomycin and neomycin. Human prostate cancer cell line DU145 (ATCC, Manassas, Va.) was originally derived from a lesion in the brain of a patient with widespread metasta...

example 2

Comparison of Imaging in Different Cell Lines

[0118]FIGS. 8A-8H show improved MR imaging in two different models of cancer using the Ligand-HK-Liposome-Mag nanocomplex. Nanocomplexes for use in this Example were prepared using the same ratios and procedures as set forth in Example 1. Human breast cancer MDA-MB-435 (FIG. 8E-8H) or human prostate cancer cell line (DU145) (FIG. 8A-8D) cells were subcutaneously injected on the lower back, of female athymic nude mice. Free MAGNEVIST®, or the TfRscFv-liposome nanocomplex (scLip-Mag), or the TfRscFv-HK-liposome nanocomplex (scLip-HK-Mag) comprising the HoKc peptide, containing the same dose of MAGNEVIST® were i.v. injected (via the tail vein) into each of the three mice on three consecutive days. This amount of MAGNEVIST® is equivalent to twice the dose that would be administered to a human patient. The total volume of solution administered in all cases was 400 μl. A baseline scan was performed just prior to administration of both nanocompl...

example 3

Comparison of Dynamic MRI Scans of Subcutaneous PANC-1 Tumors after Systemic Injection of Free (Uncomplexed) or TJRScFv-Lip-MAGNEVIST®

[0120]The following experiments were performed to compare the rate and level of uptake and washout between free (uncomplexed) and TfRscFv-Lip-Mag in tumors after systemic delivery. Subcutaneous xenograft tumors of PANC-1 were induced in female athymic nude mice by injection of 1 to 2×107 PANC-1 cells suspended in MATRIGEL™ collagen basement membrane matrix (BD Biosciences). Approximately 2.5-3 weeks later, the animals were used for imaging. Cationic liposome (DOTAP:DOPE) was prepared by the ethanol injection method as previously described (see U.S. Published Patent Application No. 2003 / 0044407; Xu L, et al., Molecular Cancer Therapeutics 1:337-346 (2002) the disclosures of each of which are incorporated herein by reference). The targeting moiety used in these studies is the anti-transferrin receptor single chain antibody fragment (TfRscFv).

[0121]To en...

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Abstract

The present invention is in the fields of drug delivery, cancer treatment and diagnosis and pharmaceuticals. This invention provides a method of making antibody- or antibody fragment-targeted immunoliposomes for the systemic delivery of molecules to treat and image diseases, including cancerous tumors. The invention also provides immunoliposomes and compositions, as well as methods of imaging various tissues. The liposome complexes are useful for encapsulation of imaging agents, for example, for use in magnetic resonance imaging. The specificity of the delivery system is derived from the targeting antibodies or antibody fragments.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application is a continuation of U.S. application Ser. No. 11 / 583,708, filed Oct. 20, 2006, which claims the benefit of U.S. Provisional Patent Application No. 60 / 728,303, filed Oct. 20, 2005, the disclosures of each of which are incorporated by reference herein in their entireties.[0002]The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Dec. 6, 2013, is named 2474—0006US2_Sequence_Listing.txt and is 974 bytes in size.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]The present invention is in the fields of drug delivery, cancer treatment and diagnosis and pharmaceuticals. This invention provides a method of making antibody- or antibody fragment-targeted immunoliposomes for the systemic delivery of molecules to treat and image diseases, including cancerous tumors. The inventi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K51/12A61K49/18
CPCA61K49/0002A61K9/1272A61K49/1812A61K51/1234A61K49/0466
Inventor CHANG, ESTHER H.PIROLLO, KATHLEEN F.
Owner GEORGETOWN UNIV
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