Method for regressing pancreatic tumor by a liposomal formulation along with DNA vaccines
Inventors
Madamsetty, Vijay Sagar • Chaudhuri, Arabinda • Mukhopadhyay, Debabrata
Assignees
Council of Scientific and Industrial Research CSIR • Mayo Clinic
Publication Number
US-10611796-B2
Publication Date
2020-04-07
Expiration Date
2037-03-16
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Abstract
The present invention discloses a Plectin-1 receptor targeting novel cationic KTLLPTPK(SEQ ID NO: 1)-lipopeptide. The present invention further discloses a liposomal formulation comprising the cationic KTLLPTPK(SEQ ID NO: 1)-lipopeptide, at least two co-lipids, a therapeutic agent, and a pharmaceutically acceptable carrier. The present invention also provides a method for regressing established pancreatic tumors comprising administering a therapeutically effective amount of the liposomal formulation with the therapeutic agents in combination with targeted genetic immunization (DNA vaccination) i.e. by immunizing mice with electrostatic complexes (direct in-vivo DC-targeting cationic liposomes) of DNA vaccines encoding mesothelin (p-CMV-MSLN).
Core Innovation
The present invention provides a novel liposomal formulation comprising a cationic KTLLPTPK (SEQ ID NO: 1)-lipopeptide, at least two co-lipids, a therapeutic agent, and a pharmaceutically acceptable carrier. The lipopeptide includes a KTLLPTPK octapeptide head-group designed to target the Plectin-1 receptor, which is overexpressed on pancreatic cancer cells. This structure, including hydrophobic groups directly linked to a positively charged nitrogen and a polar KTLLPTPK head-group connected via a lysine spacer, facilitates selective interaction and uptake by tumor cells.
The invention addresses the formidable challenge of regressing established pancreatic tumors, a disease characterized by low survival rates and difficulty in achieving effective drug delivery. Traditional methods of delivering cytotoxic drugs or DNA vaccines show limited success due to multidrug resistance, toxicities, and inefficiencies in targeting antigen-presenting cells, especially with previous ex vivo or indirect in vivo delivery approaches.
To solve these problems, the invention discloses a combination approach: administering the targeted liposomal formulation with encapsulated therapeutic agents (such as curcumin and gemcitabine) together with an in vivo dendritic cell targeting DNA vaccine encoding mesothelin (p-CMV-MSLN). The co-administration results in synergistic regression of established pancreatic tumors, confirmed in orthotopic mouse tumor models. This dual-therapy exploits the selective targeting of the liposomal drug for chemotherapy and the direct immunization provided by dendritic cell-targeted DNA vaccination, overcoming prior limitations.
Claims Coverage
The patent contains one independent claim outlining two principal inventive features.
Liposomal formulation with cationic KTLLPTPK-lipopeptide and co-lipids
A liposomal formulation comprising a cationic lipopeptide with formula A (KTLLPTPK head-group), a first co-lipid, a second co-lipid, a pharmaceutically acceptable carrier, and a therapeutic agent. The components are combined in a specified molar ratio of 0.5:1:0.25:0.02:1-10. The lipopeptide’s designed targeting sequence enables selective delivery to pancreatic tumor cells via Plectin-1 receptor interaction.
Combination therapy with in vivo dendritic cell targeting DNA vaccine
A method involving the administration of the above liposomal formulation in combination with an in vivo dendritic cell targeting DNA vaccine that encodes mesothelin (p-CMV-MSLN). This combination is administered to a subject in need via intravenous or subcutaneous injection, intending to synergistically regress established pancreatic tumors through both targeted chemotherapy and direct immunomodulation.
In summary, the claims cover a synergistic regimen involving a specifically formulated, Plectin-1-targeting liposomal drug carrier in combination with dendritic cell-targeted DNA immunization for effective regression of pancreatic tumors.
Stated Advantages
The invention enables targeted delivery of cytotoxic and therapeutic agents (such as DNA, RNA, drugs, proteins) directly to both tumor endothelial cells and tumor cells, particularly via the Plectin-1 receptor.
Tumor growth inhibition is achieved through the targeted co-delivery of curcumin and gemcitabine in pancreatic cancer, with enhanced efficacy when combined with in vivo dendritic cell targeted DNA vaccination.
Simultaneous application of targeted chemotherapy and direct in-vivo cancer immunotherapy enables regression of established tumors, an outcome not achieved by either therapy alone.
The approach avoids toxic side effects associated with single chemotherapeutics, eliminates the need for isolating and reinfusing dendritic cells, and reduces non-specific drug delivery to non-target organs.
The methods provide a platform technology for regressing tumors through combined chemotherapeutic and immunomodulatory strategies, streamlining treatment protocols.
Documented Applications
Regressing established pancreatic tumors in human or animal subjects by administering the liposomal formulation containing cationic KTLLPTPK-lipopeptide with co-encapsulated curcumin and gemcitabine in combination with dendritic cell targeted DNA vaccines encoding mesothelin.
Selective delivery of therapeutic agents such as DNA, RNA, proteins, or cytotoxic drugs to pancreatic tumor cells via Plectin-1 receptor targeting.
Inducing apoptosis in pancreatic tumor cells and inhibiting tumor growth in syngeneic orthotopic mouse models for pancreatic cancer.
Simultaneous use of the formulation for both targeted chemotherapy and immunotherapy (genetic immunization), enabling regression of established tumors and improved survival outcomes.
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