IPA-3-loaded liposomes and methods of use thereof
Inventors
Rammohan Shenoy, Somanath • Cummings, Brian S. • Najahi-Missaoui, Wided
Assignees
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Publication Number
US-11969396-B2
Publication Date
2024-04-30
Expiration Date
Abstract
Lipid-based delivery vehicles are provided. Nanoparticulate compositions typically including a p21 activated kinase (PAK) inhibitor and a lipid-based delivery vehicle are also provided. In preferred embodiments, the lipid-based delivery vehicle is a liposome, most preferably a sterically-stabilized liposome. Typically the lipid-based delivery vehicle includes one or more phospholipids, and optionally a sterol. In some embodiments, at least one of the phospholipids is PEGylated. In particular embodiments, the lipid-based delivery vehicle includes DSPC, DSPE-PEG2000, and cholesterol. In specific embodiments, the ratio of DSPC, DSPE-PEG, and cholesterol is 9:1:5. The nanoparticulate composition typically includes a PAK inhibitor, preferably a PAK-1 inhibitor such as IPA-3 or a derivative, prodrug, or pharmaceutically acceptable salt thereof. Methods of use, for example methods of treating cancer, particularly prostate and breast cancer by administering the composition to subjects in need thereof, are also provided.
Core Innovation
The invention relates to a nanoparticulate composition that comprises a p21 activated kinase (PAK) inhibitor together with a lipid-based delivery vehicle. The p21 activated kinase (PAK) inhibitor is Inhibitor targeting P21-activated kinase-1 (PAK1) activation-3 (IPA-3), a prodrug, or a pharmaceutically acceptable salt thereof. The lipid-based delivery vehicle is a liposome that consists essentially of DSPC and/or DSPE, at least one pegylated lipid, and cholesterol.
The disclosed approach is directed to improving in vivo stability/half-life and reducing dosing frequency for cancer therapy by using sterically stabilized PEGylated (stealth) liposomes to deliver IPA-3. The patent describes sterically stabilized/stealth liposome formulations as nanoparticulate compositions, including defined physicochemical characteristics and particle diameter.
The document further characterizes the resulting formulations for drug retention and therapeutic effects in vitro and in vivo. IPA-3 loaded into the liposomes shows improved retention compared with free drug behavior, with in vitro effects including cytotoxicity, apoptosis, and necrosis, and with in vivo efficacy reported in a prostate cancer xenograft model with increased apoptosis compared with free IPA-3 or empty liposomes.
Claims Coverage
The independent claim covers a nanoparticulate composition combining a PAK inhibitor (IPA-3, IPA-3 prodrug, or a pharmaceutically acceptable salt) with a liposome delivery vehicle consisting essentially of DSPC and/or DSPE, at least one pegylated lipid, and cholesterol. Main inventive features include the specified inhibitor identity and the essential liposome lipid/PEG/cholesterol components, with dependent refinements for physicochemical characteristics, particle diameter, pegylated DSPE, and higher PAK-1 expression in cancer cells.
IPA-3 as a PAK inhibitor in the nanoparticulate composition
The p21 activated kinase (PAK) inhibitor is Inhibitor targeting P21-activated kinase-1 (PAK1) activation-3 (IPA-3), a prodrug, or a pharmaceutically acceptable salt thereof.
Essential liposome composition with DSPC/DSPE, pegylated lipid, and cholesterol
The lipid-based delivery vehicle is a liposome which consists essentially of 1, 2-distearoyl-sn-glycero-3-phosphatidylcholine (DSPC) and/or 1, 2-distearoyl -sn-glycero-3-phosphatidylethanolamine (DSPE), at least one pegylated lipid, and cholesterol.
Defined physicochemical characteristics
The nanoparticulate composition includes a polydispersity index (PDI) and/or zeta potential.
Defined particle diameter
The nanoparticulate composition has a diameter of about 75 nm to about 500 nm.
Pegylated DSPE as the pegylated lipid
The pegylated lipid component is pegylated 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine (DSPE).
Higher PAK-1 expression in cancer cells
The cancer includes cancer cells expressing PAK-1 at a higher expression level than normal cells of the same type.
Overall, the claim set centers on a liposome-based nanoparticulate composition delivering the PAK1 inhibitor IPA-3, or a prodrug or salt thereof, using a liposome defined essentially by DSPC and/or DSPE, a pegylated lipid, and cholesterol, with dependent refinements for particle properties and cancer selection based on higher PAK-1 expression.
Stated Advantages
Improves in vivo stability/half-life.
Reduces dosing frequency.
Shows tumor growth inhibition in vivo, reported for a prostate cancer xenograft model.
Increases apoptosis compared with free IPA-3 or empty liposomes.
Does not have significant body weight effects, reported in vivo.
Documented Applications
Cancer therapy using the sterically stabilized PEGylated liposome formulation loaded with IPA-3, particularly for prostate cancer and breast cancer cell line contexts.
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