Pharmaceutical compositions comprising POH derivatives
Inventors
Chen, Thomas • Levin, Daniel • Puppali, Satish
Assignees
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Publication Number
US-12383621-B2
Publication Date
2025-08-12
Expiration Date
Abstract
The present invention provides for a perillyl alcohol (POH) carbamate, such as POH-Rolipram. The present invention also provides for a method of treating a disease such as cancer, by delivering to a patient a therapeutically effective amount of POH-Rolipram.
Core Innovation
The described work forms and characterizes perillyl alcohol carbamate conjugates, including temozolomide-POH carbamate (TMZ-POH) and rolipram POH carbamate (POH-rolipram/NEO214). The document reports chemical synthesis and characterization by 1H NMR and mass spectrometry for the POH carbamate constructs, together with comparative cytotoxicity outcomes using in vitro assays against glioma models and related cell lines.
The described results report that TMZ-POH and POH-rolipram/NEO214 substantially enhance glioma cell killing versus the parent drugs, with lower IC50 values across multiple cell lines, including TMZ-resistant/chemoresistant glioma models. The document further states limited toxicity to normal astrocytes and brain endothelial cells, and it includes colony-forming assay data supporting potency on sensitive and resistant cells.
For NEO214, the document reports mechanistic findings including induction of apoptosis with PARP and cleaved caspase-7, ER stress with GRP78, CHOP, and ATF3, and DNA damage indicated by p-H2AX. It also reports autophagy marker changes involving LC3 and p62, cell-cycle pathway modulation involving cyclins, and mitogenic pathway inhibition, together with DR5 upregulation/localization as a potential sensitization mechanism.
The document includes an in vivo nude mouse subcutaneous glioma study for POH derivatives, reporting potency for the POH derivatives and stating that butyryl-POH is most effective. The overall described content connects POH carbamate conjugates and their mechanistic cellular effects to enhanced anti-glioma activity in vitro and in vivo.
Claims Coverage
The claims cover one inventive feature in the independent claim, with dependent claims adding four further limitations.
Nasal delivery of perillyl alcohol carbamate conjugated with rolipram for nervous system tumor treatment
A method for treating a cancer in a mammal by administering to the mammal a therapeutically effective amount of perillyl alcohol carbamate using a nasal delivery device, where the perillyl alcohol carbamate comprises perillyl alcohol conjugated with rolipram, and where the cancer is a tumor of the nervous system.
Intranasal delivery device type refinement
The method further specifies that the nasal delivery device is one of several listed intranasal delivery device types.
Glioblastoma as the nervous system tumor
The method further specifies that the tumor of the nervous system is a glioblastoma.
Radiation in combination with nasal perillyl alcohol carbamate treatment
The method further includes treating the mammal with radiation.
Chemotherapeutic agent delivered with the nasal perillyl alcohol carbamate treatment
The method further includes delivering a chemotherapeutic agent to a mammal.
The independent claim covers nasal delivery of a therapeutically effective amount of perillyl alcohol carbamate conjugated with rolipram for treatment of a nervous system tumor. Dependent claims further narrow the nasal delivery device types, specify glioblastoma, and add radiation and delivery of a chemotherapeutic agent.
Stated Advantages
Substantially enhances glioma cell killing versus the parent drugs.
Achieves lower IC50 values across multiple cell lines, including TMZ-resistant/chemoresistant glioma models.
Exhibits limited toxicity to normal astrocytes and brain endothelial cells.
Demonstrates potency in an in vivo nude mouse subcutaneous glioma study, with butyryl-POH reported as most effective.
Documented Applications
In vitro cytotoxicity studies against glioma cell lines, including TMZ-resistant/chemoresistant glioma models.
Mechanistic evaluation of NEO214 in cellular assays, including apoptosis, ER stress, DNA damage, autophagy, cell-cycle modulation, and mitogenic pathway inhibition.
In vivo nude mouse subcutaneous glioma study for POH derivatives.
Colony-forming assays supporting potency on sensitive and resistant cells.
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