Binary lipid bilayer-containing vesicles comprising embedded cytotoxic agents and methods of making and using the same
Inventors
Assignees
United States, Represnted By Secretary Department Of Health And Human Services AS • US Department of Health and Human Services
Publication Number
US-12178907-B2
Publication Date
2024-12-31
Expiration Date
2039-07-11
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Embodiments of vesicles comprising embedded cytotoxic agents are disclosed, as well as methods of making and using the vesicles. Pharmaceutical compositions including the vesicles also are disclosed. The vesicles include a binary lipid bilayer surrounding a cavity, wherein the vesicle binary lipid bilayer includes (i) a non-bilayer forming lipid (or combination of non-bilayer forming lipids) and a PEGylated lipid; and (i) a cytotoxic agent embedded within the vesicle wall.
Core Innovation
The invention disclosed is a vesicle comprising a binary lipid bilayer that includes an alkyne-containing phospholipid and a PEGylated lipid, with a cytotoxic agent embedded within this bilayer. The binary lipid bilayer specifically excludes lipids other than the defined alkyne-containing phospholipids or PEGylated lipids. Such vesicles can incorporate cytotoxic agents like tetrapyrrollic compounds or camptothecin compounds at high concentrations, providing stable delivery systems with defined size ranges and high PEGylated lipid content, which enhance tumor accumulation and stability.
The problem addressed by the invention relates to the limitations of conventional photodynamic therapy (PDT) nanoplatforms and liposomal drug delivery systems. Conventional platforms typically have structural features that limit their therapeutic application and tumor accumulation, including limited PEGylated lipid incorporation due to structural constraints, leading to instability and insufficient tumor targeting. There is a need for vesicle platforms that exhibit preferential tumor uptake, plasma stability, longer shelf life, and high loading capacity for cytotoxic agents while reducing complexity and cost.
Claims Coverage
The claims include 14 inventive features focused on the composition of vesicles comprising a binary lipid bilayer with specific lipid components and embedded cytotoxic agents, as well as methods of using and administering these vesicles.
vesicle composition comprising binary lipid bilayer and embedded cytotoxic agent
A vesicle containing a binary lipid bilayer comprising an alkyne-containing phospholipid and a PEGylated lipid, with a cytotoxic agent embedded within the bilayer.
pegylated lipid proportion in binary lipid bilayer
The binary lipid bilayer comprises greater than 6 mol % to 20 mol %, or specifically 10 mol % to 20 mol % of the PEGylated lipid.
specific ratio of total lipid to cytotoxic agent
The alkyne-containing phospholipid, PEGylated lipid, and cytotoxic agent together are present at a ratio of 1:0.05 (total lipid to cytotoxic agent).
alkyne-containing phospholipid identity
The alkyne-containing phospholipid is either an alkyne-containing phosphocholine lipid or a mixture of alkyne-containing phosphocholine and phosphoethanolamine lipids.
specific alkyne-containing phospholipids used
The alkyne-containing phosphocholine lipid is DC8,9PC, and the alkyne-containing phosphoethanolamine lipid is DC8,9PE.
pegylated lipid identity and size range
The PEGylated lipid is a PEGylated DSPE lipid with a PEG group molecular weight ranging from 500 Da to 5000 Da, or specifically 1000 Da to 3000 Da, with DSPE-PEG2000 as a particular example.
cytotoxic agents included
The cytotoxic agent is selected from tetrapyrrollic compounds, camptothecin compounds, paclitaxel, daunorubicin, methotrexate, vincristine, etoposide, sorafenib, erlotinib, imatinib, or any combination thereof.
specific tetrapyrrollic compounds
Tetrapyrrollic compounds include HPPH, chlorin e6 (Ce6), Pheophorbide a, Temoporfn, Verteporfin, or any combination thereof.
specific camptothecin compounds
Camptothecin compounds include camptothecin, silatecan, SN-38, topotecan, irinotecan, 9-nitro-camptothecin, lurtotecan, exatecan, gimatecan, and karenitecin.
veicle composition with binary lipid bilayer consisting solely of alkyne-containing lipid, PEGylated lipid, and cytotoxic agent
A vesicle comprising a binary lipid bilayer consisting only of an alkyne-containing lipid, PEGylated lipid, and an embedded cytotoxic agent.
specific vesicle composition comprising DSPE-PEG2000, DC8,9PC, DC8,9PE and cytotoxic agents
A vesicle comprising a binary lipid bilayer with DSPE-PEG2000 and DC8,9PC, or a combination of DC8,9PC and DC8,9PE, with embedded HPPH, Ce6, and/or camptothecin, free of other lipids.
method of photoactivation using near-infrared light
A method providing the vesicle and irradiating it with targeted near-infrared light (650-670 nm) at selected intensity (1 mW to 500 mW) and effective period (at least 30 seconds) to activate the cytotoxic agent.
method of treatment involving administration and targeted irradiation
A method identifying a subject with a treatable condition, administering the vesicle intravenously or as a pharmaceutical composition, and directing targeted light—externally or internally by endoscope or fiber optic catheter—toward a tumor site to induce tumor regression.
method for impairing tumor growth using the vesicle and light activation
A method comprising administering a therapeutically effective amount of the vesicle and irradiating the tumor site with near-infrared light to activate the cytotoxic agent and promote reactive oxygen species formation, thereby inhibiting tumor growth.
The claims comprehensively cover vesicles comprising binary lipid bilayers formed from specific alkyne-containing phospholipids and PEGylated lipids incorporating cytotoxic agents such as tetrapyrrollic and camptothecin compounds, with defined lipid to agent ratios and PEGylation levels, along with methods of applying near-infrared light for therapeutic activation and methods of treatment via administration and irradiation.
Stated Advantages
The vesicles exhibit preferential tumor uptake and highly efficient tumor accumulation.
They maintain stability upon storage at ambient temperatures, leading to longer shelf lives.
The vesicles accommodate high amounts of PEGylated lipids, enhancing plasma stability and reducing uptake by the mononuclear phagocytic system.
Embedding cytotoxic agents at high concentration within the binary lipid bilayer increases therapeutic efficacy and enables controlled photoactivation.
Photoactivation enables targeted cytotoxic agent activation, reducing systemic toxicity and improving side effect profiles.
The vesicles exhibit stability in the presence of serum proteins, preventing premature drug release.
Compared to conventional formulations, the vesicle-formulated cytotoxic agents demonstrate improved tumor regression and animal survival with no tumor recurrence.
Documented Applications
Targeted photodynamic therapy (PDT) for cancer treatment by intravenously administering vesicles with embedded cytotoxic agents to tumor-bearing subjects followed by targeted near-infrared light irradiation to activate the agents at the tumor site.
Use of the vesicles for delivering cytotoxic agents such as HPPH, chlorin e6, camptothecin, and analogs to tumors to inhibit tumor growth, induce tumor regression and enhance survival in animal cancer models.
Nano-imaging tools for monitoring tumor targeting and biodistribution using near-infrared fluorescent lipid probes incorporated in the vesicles.
Potential applications as pathogen diagnostics, oral vaccines, and biomimetics, as mentioned in the disclosure.
Interested in licensing this patent?