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(12) Patent Application Publication (10) Pub. No.: US 2014/0363497 A1 Sengupta Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2014/0363497 A1 Sengupta Et Al US 20140363497A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0363497 A1 Sengupta et al. (43) Pub. Date: Dec. 11, 2014 (54) NANOCELL DRUG DELIVERY SYSTEM A613 L/704 (2006.01) A647/48 (2006.01) (71) Applicant: Massachusetts Institute of Technology, A6II 45/06 (2006.01) Cambridge, MA (US) (52) U.S. Cl. O O CPC ......... A61 K9/1271 (2013.01); A61K47/48869 (72) Inventors: Shiladitya Sengupta, Waltham, MA (2013 .01): A6 IK 47/48815 (201 3 .01): A61 K (US); Ganlin Zhao, Arlington, MA 47/482 (2013.01); A61K 45/06 (2013.01); (US), Ishan Capila, Ashland, MA (US); A61 K3I/09 (2013.01); A61 K3I/704 David Eavarone, North Quincy, MA (2013.01); G0IN33/50II (2013.01); G0IN (US); Ram Sasisekharan, Cambridge, 2500/10 (2013.01) MA (US) USPC ........................... 424/450: 424/78.17; 435/32 (21) Appl. No.: 14/467,784 (57) ABSTRACT (22) Filed: Aug. 25, 2014 Nanocells allow the sequential delivery of two different thera Related U.S. Application Data peutic agents with different modes of action or different phar macokinetics. A nanocell is formed by encapsulating a nano (63) Continuation of application No. 13/745,230, filed on core with a first agent inside a lipid vesicle containing a Jan. 18, 2013, which is a continuation of application second agent. The agent in the outer lipid compartment is No. 12/780.470, filed on May 14, 2010, now aban- released first and may exert its effect before the agent in the doned, which is a continuation of application No. nanocore is released. The nanocell delivery system may be 11/070,731, filed on Mar. 2, 2005, now abandoned. formulated in pharmaceutical composition for delivery to (60) Provisional application No. 60/549,280, filed on Mar. patients Suffering from diseases such as cancer, inflammatory 2, 2004. diseases such as asthma, autoimmune diseases such as rheu matoid arthritis, infectious diseases, and neurological dis Publication Classification eases such as epilepsy. In treating cancer, a traditional anti neoplastic agent is contained in the outer lipid vesicle of the (51) Int. Cl. nanocell, and an antiangiogenic agent is loaded into the nano A 6LX 9/27 (2006.01) core. This arrangement allows the antineoplastic agent to be GOIN33/50 (2006.01) released first and delivered to the tumor before the tumors A6 IK3I/09 (2006.01) blood Supply is cut off by the antianiogenic agent. Patent Application Publication Dec. 11, 2014 Sheet 1 of 15 US 2014/0363497 A1 Patent Application Publication Dec. 11, 2014 Sheet 2 of 15 US 2014/0363497 A1 Patent Application Publication Dec. 11, 2014 Sheet 3 of 15 US 2014/0363497 A1 (A) M-N-a---Chs d Chs d O PLGA5050 d 4A (C) 1...pNC, pyridine, CHC HCO 2. Doxorubicin, DMF, TEA O OH C DC O OH OCCO HC1 o OH O O o HC CH d ch N °ul d O o O C 1.d s Doxorubicin-PLGA conjugate emulsion-solvent evaporation (B) Ultracentrifugation, sizing and phospholipid membrane coating. Combretastatin encapsulated in lipid layer. D Doxorubicin (ug) 2 (E) (F) Combretastatin (x10°ug) 200 10 t g s 5 150 a 7 kkk t sh 6 5 # as 100 4 23 ut-'i 50 S9 SY O H --T &S CS O 6 12 18 24 25 49 73 97 121 s S S$. Time8. (hours) {S Figure 3 Patent Application Publication Dec. 11, 2014 Sheet 4 of 15 US 2014/0363497 A1 Figure.4. Effect of VEGF and HGF on tumor angiogenesis in vitro, specificity of a VEGFantagonist i Turnor cells Blood vessels forning Endothelial cells Only tumor cells express green fluorescent proteins, and all nuclei are stained with PL. In a mergeimage, the tumor cells look yellow as a result ofgreen and red merging, while endothelial cells look only red, Patent Application Publication Dec. 11, 2014 Sheet 5 of 15 US 2014/0363497 A1 Figure. 5. Effect of Doxorubicin, thalidomide, and combretastatin on VEGF-induced tumor angiogenesis in vitro. Tumor cells a Blood vessels S. forming 5 O Endothelial g cells sS. r 3O > . 5 23 st g c Sc. is g - s5 e 33 > O This model allows the dissection of chemotherapeutics and anti-angiogenics, Doxorubicinkills only the yellow tumor cell, while the anti-angiogenicskill only the red endothelial cells. Patent Application Publication Dec. 11, 2014 Sheet 6 of 15 US 2014/0363497 A1 Figure. 6. Effect of Doxorubicin, thalidomide, and combretastatin on HGF-induced tumor angiogenesis in vitro. Tumor cells Propidium iodide Blood vessels rrd forming Endothelial S. cells (D This model allows the identification of exact drugs that would workin defined clinicopathological cases. Doxorubicin works like it did in the case of VEGF induced response, but unlike Fig.5., both thalidomide and combretastatin failed to inhibit the HGF-induced effect, This shows that the assay can detect unique effects of growth factors. Patent Application Publication Dec. 11, 2014 Sheet 7 of 15 US 2014/0363497 A1 Figure. 7. Effect of Doxorubicin, thalidomide, and combretastatin on VEGF-induced tumor angiogenesis in vitro, when plated on collagen. Blood vessels forming Endothelial c cells D > Tumor cells -- Patent Application Publication Dec. 11, 2014 Sheet 8 of 15 US 2014/0363497 A1 Figure.8. Effect of Doxorubicin, thalidomide, and combretastatin on HGF-induced tumor angiogenesis Blood vessels s forming . Endothelial 9 cells O Tumor cells Changing the extra-cellular matrix from matrigel to collagen results in the loss of protective function of HGF against the anti-angiogenic effects of combretastatin and thalidomide, Patent Application Publication Dec. 11, 2014 Sheet 9 of 15 US 2014/0363497 A1 (A) Y- Control 4. N Control (12h) (B) Vascular Tumor (C), component component .0 40 - T - - - - - QS 1.5 w ke X 30 a 1.0 Od 0.5 Dox-PLGA N 20 e 0.0 10 O 5 10 15 20 Dox) ug O Veh NCVeh NCND Veh NC Veh NCND A Doxorubicin - - - - - Dox-PLGA conjugate Figure 9 Patent Application Publication Dec. 11, 2014 Sheet 10 of 15 US 2014/0363497 A1 (A) Vehicle NCD+LC NCD+L(C) NC 3 cm B6/F10 melanoma 6% B16/F10 melanoma 7500 5000 2500 - f 2000 l 1500 000 500 it is tist, O t; t it is is 1, Days Days -- Veh-i-LIC)--NCD) -v- LCD) E : 220 3 5 170 8 120 Bt 70 5 O 20 s 3.99. S S CSN. \s 3. Y & -SCN Figure 10 Patent Application Publication Dec. 11, 2014 Sheet 11 of 15 US 2014/0363497 A1 () vehicle LC NCD NCD+L(C) NC LCD (B) 40 2. 230 40 9 2 al 30 20 2. 20 > 0 & 10 0. O s (E) (F) 2 - Guy VEGF as us mom or n a 9 HIF-o wrimur meuro- 3 s g B-actin unusmrau ou umm is 1 s veh Lc NCD) Lc NC LCD S. g NCD 0 & S.S.SYSSY3&S S Figure 11 Patent Application Publication Dec. 11, 2014 Sheet 12 of 15 US 2014/0363497 A1 A -- Vehicle (A) -- LIC) 9000. NCIC) 7000 5OOO 3OOO 3000 2500 2000 1500 1OOO 500 O 7 g 11 1315 17 Days (B) 12000 -- Veh 2 9000 --NC long term 2 S 6000 2 3000 0: AXA f 25 30 Days Figure 12 Patent Application Publication Dec. 11, 2014 Sheet 13 of 15 US 2014/0363497 A1 (A) Vehicle control NCD) LC NCD+L(C) LCD NCDC) (B) Vehicle control NCD) LC) NCD+LIC) LCD NCDC) (c)C (p)so a 6 Lungs s Liver 2 2 o 4 9 2.5 2 E E it E. Veh NC(DLC) NCD) NC LCD) 0. O it is +L(C) +L(C) Figure 13 Patent Application Publication Dec. 11, 2014 Sheet 14 of 15 US 2014/0363497 A1 NO2 O CH3 O CH3 -- Hous O O o OH O O -- PLGA 5050 DL 4A O p-nitrophenyl chloroformate (pNC) Pyridine, CH2Cl2 O | O CH3 O CH3 O O O O Activated PLGA Doxorubicin, DMF, TEA O OH O OH to O OH O H3C O O O CH3 O CH NH °ul O O O OH OH O Doxorubicin - PLGA conjugate Figure 14 Patent Application Publication Dec. 11, 2014 Sheet 15 of 15 US 2014/0363497 A1 SaibutarToi Release Kinetics G rizrocell asthma) E 4 C 9. 3 CD s on 2 s O s 1 --a o H Y 5 1. 150 2O Lites GS Deomethasome-release kinetics ranoel Athin : CD ke r-i- CD k o shc O H ---. 1 2D up so as a todadorsunda Hours Figure 15 US 2014/0363497 A1 Dec. 11, 2014 NANOCELL DRUG DELVERY SYSTEM treatment of cancers of the colon-rectum, esophagus, liver, pancreas, and kidney, and skin. A major problem with sys RELATED APPLICATIONS temic chemotherapy for the treatment of these types of can cers is that the systemic doses required to achieve control over 0001. The present application claims priority under 35 tumor growth frequently result in unacceptable systemic tox U.S.C. S 119(e) to U.S. provisional application, U.S. Ser. No. icity. Efforts to improve delivery of chemotherapeutic agents 60/549,280, filed Mar. 2, 2004, entitled “Nanocell Drug to the tumor site have resulted in advances in organ-directed Delivery System,” which is incorporated herein by reference. chemotherapy, for example, by continuous systemic infusion. However, continuous infusions of anticancer drugs generally BACKGROUND OF THE INVENTION have not shown a clear benefit over pulse or short-term infu 0002 The prerequisites for rational drug therapy are an sions. The anti-neoplastic or chemotherapeutic agents cur accurate diagnosis, knowledge of the pathophysiology of the rently used in the clinic include (a) alkylating agents, such as disease, the knowledge of basic pharmacotherapeutics in nor mechlorethamine, cyclophosphamide, ifosfamide, mel mal and diseased people, and the reasonable expectations of phaan, chlorambucil, hexamethylmelamine, thiotepa, buSul these relationships so that the drug's effects can be antici fan, carmustine, lomustine, Semustine, Streptozocin, dacarba pated (DiPiro et al.
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