Targeted delivery to human diseases and disorders
View Patent ↗The present invention provides a system presenting site-specific accumulation through a ligand that specifically targets a receptor overexpressed on the surface of specific cells within a target organ, like, for example, tumor cells and/or vascular cells of tumor blood vessels. Moreover, this invention provides a method where, upon internalization of the previous-mentioned system by the target cells, triggered release at a high rate of the associated agent takes place, permitting efficient intracellular delivery and, thus, increased concentration of the transported cargo at the target site. Overall, this invention provides a method for the diagnosis, prevention and treatment of human diseases and disorders.
1. A ligand-targeted delivery system comprising a ligand linked to a support carrying an agent,
wherein said ligand is a peptide comprising the amino acid sequence of F3 (SEQ ID NO: 1), wherein said support is a pH sensitive liposome,
wherein the agent is a therapeutic, diagnostic and/or imaging agent, encapsulated, entrapped or intercalated in the support, and
wherein said liposome is capable of the pH dependent intracellular release of said agent.
2. The ligand-targeted delivery system according to claim 1 , wherein said liposome comprises
dioleoylphosphatidylethanolamine, cholesteryl hemisuccinate and one or more lipids selected from the group consisting of methoxy-poly(ethylene glycol) phosphatidylethanolamine, maleimide-poly(ethylene glycol) phosphatidylethanolamine, N methylpalmitoyloleoylphosphatidylcholine, phosphatidylserine, phosphatidylcholine, palmitoyloleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylglycerol and cholesterol.
3. The ligand-targeted delivery system according to claim 1 , wherein said liposome comprises
dioleoylphosphatidylethanolamine, cholesteryl hemisuccinate, fully hydrogenated soy phosphatidylcholine, cholesterol, distearoylphosphatidylethanolamine methoxy(polyethylene glycol) (2000) and distearoylphosphatidylethanolamine maleimide(polyethylene glycol).
4. The ligand-targeted delivery system according to claim 1 , wherein said liposome comprises
dioleoylphosphatidylethanolamine, cholesteryl hemisuccinate, fully hydrogenated soy phosphatidylcholine, cholesterol, distearoylphosphatidylethanolamine methoxy(polyethylene glycol) (2000) and distearoylphosphatidylethanolamine maleimide(polyethylene glycol) at a 4:2:2:2:0.18:0.12 molar ratio.
5. The ligand-targeted delivery system according to claim 1 , wherein the therapeutic agent comprises
a cytotoxic compound, an anti-cancer compound, anti-inflammatory compound, an anti-angiogenic compound, an angiolytic compound, a vascular disrupting compound or a photodynamic therapeutic agent, or combination thereof.
6. The ligand-targeted delivery system according to claim 5 , wherein the agent is one or more of the compounds selected from the group consisting of alkylating drugs; cytotoxic antibiotics; antimetabolites; vinca alkaloids; amsacrine; altertarmine; crisantaspase; dacarbazine; temozolomide; hydroxycarbamide (hydroxyurea); pentostatin; platinum compounds; porfimer sodium; procarbazine; razoxane; taxanes; topoisomerase I inhibitors; trastuzumab; tretinoin; SN-38; ET-743; TLK 286; anti-inflammatory agents; antiangiogenic agents or angiolytic agents; ABT-627; Bay 12-9566; Benefin; Bevacizumab; BMC-275291; cartilage-derived inhibitor (CDI); CAI; CD59 complement fragment; CEP-7055; Col 3; Combretastatin A-4; Endostatin (collagenXVIII fragment); Fibronectin fragment; Gro-beta; Halofuginone; Heparinases; Heparin hexasaccharide fragment; HMV833; Human chorionicgonadotropin (hCG); IM-862; Interferon alpha/beta/gamma; Interferon inducible protein (IP-10); Interleukin-12; Kringle 5 (plasminogen fragment); Marimastat; Metalloproteinase inhibitors (TIMPs); 2-Methoxyestradiol; MMI 270 (CGS 27023A); MoAbIMC-1C11; Neovastat; NM-3; Panzem; PI-88; Placental ribonuclease inhibitor; Plasminogen activator inhibitor; Platelet factor-4 (PF4); Prinomastat; Prolactin 16 kD fragment; Proliferin-related protein (PRP); PTK 787/ZK 222594; Retinoids; Solimastat; Squalamine; SS 3304; SU 5416; SU6668; SU11248; Tetrahydrocortisol-S; tetrathiomolybdate; thalidomide; Thrombospondin-1 (TSP-1); TNP-470; Transforming growth factor-beta (TGF-b); Vasculostatin; Vasostatin (calreticulin fragment); ZD6126; ZD 6474; farnesyl transferase inhibitors (FTI); bisphosphonates; and porphyrins.
7. The ligand-targeted delivery system according to claim 6 , wherein
the alkylating drugs are one or more of cyclophosphamide, chlorambucil, melphalan, busulfan, lomustin, carmustine, chlormethine (mustine), estramustine, treosulfan, thiotepa, or mitobronitol;
the cytoxic antibotics are one or more of doxorubicin, epirubicin, aclarubicin, idarubicin, daunorubicin, mitoxantrone (mitozantrone), bleomycin, dactinomycin or mitomycin;
the antimetabolites are one or more of methotrexate, capecitabine, cytarabine, fludarabine, cladribine, gemcitabine, fluorouracil, raltitrexed (tomudex), mercaptopurine, tegafur or tioguanine;
the vinca alkaloids are one more of vinblastine, vincristine, vindesine, vinorelbine or etoposide;
the platinum compounds are one or more of carboplatin, cisplatin or oxaliplatin;
the taxanes are one more of docetaxel or paclitaxel;
the topoisomerase I inhibitors are one or both of inotecan or topotecan;
the anti-inflammatory agents are one or more of ibuprofen, aceclofenac, acemetacin, azapropazone, celecoxib, dexketoprofen, diclofenac sodium, diflunisal, cetodolac, fenbufen, fenoprofen, flubiprofen, indomethacin, acetaminocin, piroxicam, rofecoxib, sulindac, tenoxicam, tiaprofenuic acid, aspirin or benorilate;
the antiangiogenic agents or angiolytic agents are one or more of Angiostatin (plasminogen fragment), antiangiogenic antithrombin III or Angiozyme.
8. The ligand-targeted delivery system according to claim 6 , wherein the anti-inflammatory agents are one or more of ibuprofen, aceclofenac, acemetacin, azapropazone, celecoxib, dexketoprofen, diclofenac sodium, diflunisal, cetodolac, fenbufen, fenoprofen, flubiprofen, indomethacin, acetaminocin, piroxicam, rofecoxib, sulindac, tenoxicam, tiaprofenuic acid, aspirin or benorilate.
9. The ligand-targeted delivery system according to claim 1 , wherein a spacer is positioned between the ligand and the support.
10. The ligand-targeted delivery system according to claim 8 , wherein the spacer comprises a tag that facilitates recovery or identification of the liposome composition.
11. The ligand-targeted delivery system as in one of claims 1 to 6 , wherein the agent is doxorubicin.
12. The ligand-targeted delivery system according to claim 1 , wherein the agent is a radionuclide or a fluorescent molecule.