Folate Receptor-Targeted Conjugates for Treatment of Spinal Trauma

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2021-LOW-69272
Researchers at Purdue University have developed new small molecule drug conjugates for targeting neuroinflammation. Targeting is done using folate, which is actively taken up into the central nervous system, and areas of inflammation such as trauma or neurodegeneration. Unsaturated aldehydes such as acrolein, methylenedioxyamphetamine, and 4-hydroxynonenal are reactive and generate free radicals causing oxidative stress and inflammation to the CNS.

Payloads delivered by folate can act to reduce oxidative stress and reactive aldehydes like acrolein. The researchers synthesized folate conjugated to hydralazine and showed its capacity to reduce acrolein in the injured region of spinal cord injury. Furthermore, targeted delivery of folate-hydralazine does not affect blood pressure. The Purdue researchers also demonstrated the ability to target inflammation using various imaging agents, including contrast agents linked to folate such as gadolinium and technetium, and dyes linked to folate such as Cy5 and SO456. Such imaging agents showed successful uptake into areas of inflammation, and other regions of the brain including the choroid plexus, retina of the eye, and cerebrospinal fluid.

Technology Validation: The researchers demonstrated successful chemical synthesis and purification of compounds using mass spectrometry. Various imaging modalities such as PET/CT/SPECT, MRI, and fluorescence imaging showed uptake of the Folate-drug conjugates. Administration of the folate-conjugates showed statistically significant reduction in oxidative stress and acrolein levels in injured rats compared to controls. Behavioral blood pressure tests using an established tail-cuff system also showed statistical significance of the conjugates compared to injured (control) rats, which have reduced blood pressure.

Advantages:

-Reduces reactive oxygen species (ROS) including acrolein
-Delivery of imaging agents to inflamed regions of CNS
-Maintains regular blood pressure in CNS damaged rats
-Enhances imaging of CNS using contrast agents or fluorescent dyes

Applications:

-Treatment of spinal cord injury caused by oxidative stress
-Neuroimaging
-Pharmaceutical research and development
Jan 6, 2022
PCT-Patent
WO
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Jan 7, 2021
Provisional-Patent
United States
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