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5-ala for detection of brain tumors

a brain tumor and 5-ala technology, applied in the field of brain tumor detection methods, can solve the problems of inability to adequately distinguish radionecrosis from mri imaging, complex treatment and risk definition, and inability to accurately detect radionecrosis, etc., and achieve high polydispersity index, high polydispersity index, and high polydispersity index

Active Publication Date: 2016-11-10
PIOMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present patent provides methods for detecting and assessing brain tumors using a pharmaceutical composition containing 5-aminolevulinic acid (5-ALA) and detecting the presence or recurrence of brain tumors by measuring the level of conversion of 5-ALA to protoporphyrin IX (PPIX) in tumor-derived microparticles. The methods can be used to detect or measure the recurrence of glioblastoma, glioma, or other solid tumors. The biological samples used for detection can be whole blood, serum, plasma, or cerebrospinal fluid. The pharmaceutical composition can be administered orally, intravenously, or through other routes. The technical effects of the patent include improved detection and assessment of brain tumors using a novel method and the development of a pharmaceutical composition for treating such tumors.

Problems solved by technology

Currently, the differentiation of disease recurrence during the standard management of this life-threatening disease is very complex and difficult to distinguish from tumor necrosis following radiation therapy, making treatment and definition of risk very complex and inaccurate
However, life expectancy is typically only 12-16 months due to the challenges to treatment including the tentacle-like protrusions of the tumor which are difficult to excise and the limited drug access due to the blood-brain barrier.
At present MRI imaging is unable to adequately discriminate between radio-necrosis due to radiation treatment and recurrence of the solid brain tumor.
These processes have significant impact on patient welfare and cost of care.
However, it is unknown whether 5-ALA signal can be detected non-invasively.

Method used

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  • 5-ala for detection of brain tumors
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  • 5-ala for detection of brain tumors

Examples

Experimental program
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Effect test

example 1

Detection and Characterization of Blood-Derived Microparticles from 5-ALA Treated GBM Patients

[0064]This Example demonstrates detection of a small molecule drug following oral dosing. The drug can be uptaken by tumor cells, enzymatically modified, and shed back into circulating microparticles within hours of dosing. Furthermore, the enzymatic modification of the small molecule drug in the tumor cells was detectable by fluorescence from blood-derived microparticles.

[0065]The purpose of this study was to (i) isolate nanometer-diameter microparticles from the serum of glioblastoma (GBM) patients that have taken Gliolan™ PO, (ii) quantify their number using two different isolation methods (ddH2O and PBS-based chromatography) and (iii) assess whether or not these microparticles contain detectable levels of endogenous fluorescence when excited with a UV laser.

[0066]Gliolan® (5-aminolevulinic acid hydrochloride) is currently approved in Europe for the intraoperative visualization of malign...

example 2

U87 Cell Line Converts 5-ALA to PPIX Via a CPOX-Mediated Conversion Process which can be Monitored in Shed Microparticles

[0136]This example demonstrates that U87 cell cultures actively convert 5-ALA to PPIX, that these cells produce coproporphyrinogen III oxidase (CPOX protein), and that CPOX proteins and PPIX are present in shed microparticles in cancer cell lines.

In Vitro Studies in U87

[0137]U87 cells representative of GBM tumors grown in T-75 flasks, in the absence of serum, were exposed to 5-aminolevulinic acid (5-ALA; 250 μg / ml) for 4 or 24 hours. Following exposure, cells were subjected to fluorescent excitation in a LSRII flow cytometer with an excitation at 406 nM violet wave length. Filter specifications were set at either 450 / 50, or set at 610 / 20 for the detection of protoporphyrin IX (PPIX).

[0138]It was found that the mean fluorescence index (MFI), as a function of time, did not change in the absence of 5-ALA. In contrast, MFI increased following exposure to 5-ALA observe...

example 3

Detection of GBM by Administration of Gliolan™

[0142]A patient is treated for GBM by surgical resection, external beam radiation, and temozolomide.

[0143]Per hospital standard protocol, the patient is evaluated on a regular basis (monthly) for clinical symptoms of disease recurrence with observational and MRI evaluation for GBM recurrence.

[0144]Gliolan™ (5-ALA) is administered at a dosage of 20 mg / kg three hours prior to the time scheduled for the blood draw.

[0145]Blood is drawn and allowed to coagulate to produce serum or spun at 1000 g for 5 minutes to produce plasma. The biological fluid is frozen at −80 C and preserved for later processing. Microparticles are isolated using size exclusion chromatography with 2% agarose as the solid phase. Double distilled H2O, (100% v / v) or PBS is used as mobile phase with a serum or plasma load volume <2% of bed volume and elution separation for molecular weight entities validated with protein standards.

[0146]5-ALA-mediated fluorescence associate...

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Abstract

The present disclosure relates to methods for detecting brain tumors and assessing the recurrence of such tumors by administering a pharmaceutical composition comprising 5-aminolevulinic acid (5-ALA) and detecting the conversion of 5-ALA to protoporphyrin IX (PPIX) associated with brain-derived microparticles.

Description

CROSS REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 656,945, which is herein incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The present disclosure relates to methods for detecting brain tumors and assessing the presence and recurrence of such tumors.BACKGROUND[0003]The most common form of the cancer originating in the brain is the most aggressive and advanced Stage IV variety called glioblastoma, Lower grade gliomas often progress to later become Stage IV GBMs. Currently, the differentiation of disease recurrence during the standard management of this life-threatening disease is very complex and difficult to distinguish from tumor necrosis following radiation therapy, making treatment and definition of risk very complex and inaccurate[0004]The current standard treatment regimen for GBM includes surgical resection, external beam radiation, and oral chemotherapy. However, life expectancy is typic...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12Q1/26C12Q1/527C12Q1/48
CPCC12Q1/26C12Q1/527C12Q1/48G01N33/57484C12Y103/03G01N33/94G01N2333/90206
Inventor EZRIN, ALAN M.
Owner PIOMA
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