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US-12616715-B2 - Nanotherapy targeting RHAMM-positive tumors

US12616715B2US 12616715 B2US12616715 B2US 12616715B2US-12616715-B2

Abstract

The present technology is directed to nanoparticle compositions and methods useful in treating RHAMM-positive cancers. Such nanoparticle compositions include a plurality of nanoparticles where each nanoparticle includes (i) a particle core with an outer surface; a first layer coating the outer surface of the particle core, the first layer including one or both of poly-L-lysine and poly-L-arginine and optionally including a fluorescent dye; a second layer coating the first layer, the second layer including one or more siRNA that inhibit expression of Bcl-2, inhibit expression of Bcl-xL (BCL2L1), inhibit expression of MCL1, inhibit expression of Bcl-w (BCL2L2), inhibit expression of Bcl-b (BCL2L10), and/or inhibit expression of BFL1 (BCL2A1); a third layer coating the second layer, the third layer including an apoptotic peptide and optionally including a fluorescent dye; and a fourth layer coating the third layer, the fourth layer including hyaluronic acid or a pharmaceutically acceptable salt thereof (HA); and where the plurality of nanoparticles has an intensity-weighted average diameter as determined by dynamic light scattering from about 100 nm to about 300 nm; or (ii) a particle core with an outer surface; a first layer coating the outer surface of the particle core, the first layer including an apoptotic peptide and optionally including a fluorescent dye; a second layer coating the first layer, the second layer including one or more siRNA that inhibit expression of Bcl-2, inhibit expression of Bcl-xL (BCL2L1), inhibit expression of MCL1, inhibit expression of Bcl-w (BCL2L2), inhibit expression of Bcl-b (BCL2L10), and/or inhibit expression of BFL1 (BCL2A1); a third layer coating the second layer, the third layer including one or both of poly-L-lysine and poly-L-arginine and optionally including a fluorescent dye; and a fourth layer coating the third layer, the fourth layer including hyaluronic acid or a pharmaceutically acceptable salt thereof (HA); and where the plurality of nanoparticles has an intensity-weighted average diameter as determined by dynamic light scattering from about 100 nm to about 300 nm.

Inventors

  • Ching-Hsuan Tung
  • Yi-Chieh Nancy Du
  • Seung Koo Lee
  • Xiang Chen

Assignees

  • CORNELL UNIVERSITY

Dates

Publication Date
20260505
Application Date
20210423

Claims (20)

  1. 1 . A method for treating a subject suffering from a RHAMM-positive cancer, wherein the method comprises administering to the subject an effective amount of a nanoparticle composition to treat the RHAMM-positive cancer; the nanoparticle composition comprising a plurality of nanoparticles where each nanoparticle comprises a particle core with an outer surface; a first layer coating the outer surface of the particle core, the first layer comprising poly-L-lysine with a weight-average molecular weight of about 40,000 to about 70,000 and optionally comprising poly-L-arginine and optionally comprising a fluorescent dye; a second layer coating the first layer, the second layer comprising one or more siRNA that inhibit expression of Bcl-xL, inhibit expression of MCL1, inhibit expression of Bcl-w, inhibit expression of Bcl-b, and/or inhibit expression of BFL1, wherein the siRNA has the sequence of 5′-GGUAUUGGUGAGUCGGAUCdTdT-3′ (SEQ ID NO. 2) or 5′-GAUCCGACUCACCAAUACCdTdT-3′ (SEQ ID NO. 3); a third layer coating the second layer, the third layer comprising an apoptotic peptide having the sequence of KLAKLAKKLAKLAKKLAKLAKKLAKLAK (SEQ ID NO. 1), and optionally comprising a fluorescent dye; and a fourth layer coating the third layer, the fourth layer comprising hyaluronic acid or a pharmaceutically acceptable salt thereof; and wherein the plurality of nanoparticles has an intensity-weighted average diameter as determined by dynamic light scattering from about 100 nm to about 300 nm.
  2. 2 . The method of claim 1 , wherein the RHAMM-positive cancer is a RHAMM B -positive cancer.
  3. 3 . The method of claim 2 , wherein the RHAMM B -positive cancer comprises one or more of a colon cancer, a colorectal cancer, a gastric cancer, an endometrial cancer, a prostate cancer, a breast cancer, a brain cancer, an ovarian cancer, a pancreatic cancer, and a lung cancer.
  4. 4 . The method of claim 2 , wherein the RHAMM B -positive cancer is a pancreatic neuroendocrine tumor, a lung adenocarcinoma, a squamous lung carcinoma, non-small cell lung cancer, small cell carcinoma of the lung, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer (such as castration resistant prostate cancer), a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, a glioma, breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a serous carcinoma, or a combination of any two or more thereof.
  5. 5 . A nanoparticle composition comprising a plurality of nanoparticles, each nanoparticle comprising a particle core with an outer surface; a first layer coating the outer surface of the particle core, the first layer comprising poly-L-lysine with a weight-average molecular weight of about 40,000 to about 70,000 and optionally comprising poly-L-arginine and optionally comprising a fluorescent dye; a second layer coating the first layer, the second layer comprising one or more siRNA that inhibit expression of Bcl-xL, inhibit expression of MCL1, inhibit expression of Bcl-w, inhibit expression of Bcl-b, and/or inhibit expression of BFL1, wherein the siRNA has the sequence of 5′-GGUAUUGGUGAGUCGGAUCdTdT-3′ (SEQ ID NO. 2) or 5′-GAUCCGACUCACCAAUACCdTdT-3′ (SEQ ID NO. 3); a third layer coating the second layer, the third layer comprising an apoptotic peptide having the sequence of KLAKLAKKLAKLAKKLAKLAKKLAKLAK (SEQ ID NO. 1) and optionally comprising a fluorescent dye; and a fourth layer coating the third layer, the fourth layer comprising hyaluronic acid or a pharmaceutically acceptable salt thereof; and wherein the plurality of nanoparticles has an intensity-weighted average diameter as determined by dynamic light scattering from about 100 nm to about 300 nm.
  6. 6 . The nanoparticle composition of claim 5 , wherein the nanoparticle composition is formulated for one or both of intravenous administration and intratumoral administration.
  7. 7 . The nanoparticle composition of claim 5 , wherein the particle core is a gold particle core, where the gold particle core in the plurality of nanoparticles has an intensity-weighted average diameter as determined by dynamic light scattering from about 30 nm to about 50 nm.
  8. 8 . The nanoparticle composition of claim 5 , wherein first layer has an average thickness of about 30 nm to about 40 nm.
  9. 9 . The nanoparticle composition of claim 5 , wherein the second layer has an average thickness of about 6 nm to about 20 nm.
  10. 10 . The nanoparticle composition of claim 5 , wherein the third layer has an average thickness of about 6 nm to about 20 nm.
  11. 11 . The nanoparticle composition of claim 5 , wherein the fourth layer has an average thickness of about 10 nm to about 40 nm.
  12. 12 . The nanoparticle composition of claim 5 , wherein the fourth layer comprises sodium hyaluronate.
  13. 13 . The nanoparticle composition of claim 5 , wherein the fourth layer comprises sodium hyaluronate with a weight-average molecular weight of about 100,000 to about 150,000.
  14. 14 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a nanoparticle composition of claim 5 to treat RHAMM-positive cancer in a subject.
  15. 15 . A nanoparticle composition comprising a plurality of nanoparticles, each nanoparticle comprising a particle core with an outer surface; a first layer coating the outer surface of the particle core, the first layer comprising an apoptotic peptide having the sequence of KLAKLAKKLAKLAKKLAKLAKKLAKLAK (SEQ ID NO. 1) and optionally comprising a fluorescent dye; a second layer coating the first layer, the second layer comprising one or more siRNA that inhibit expression of Bcl-xL, inhibit expression of MCL1, inhibit expression of Bcl-w, inhibit expression of Bcl-b, and/or inhibit expression of BFL1, wherein the siRNA has the sequence of 5′-GGUAUUGGUGAGUCGGAUCdTdT-3′ (SEQ ID NO. 2) or 5′-GAUCCGACUCACCAAUACCdTdT-3′ (SEQ ID NO. 3); a third layer coating the second layer, the third layer comprising poly-L-lysine with a weight-average molecular weight of about 40,000 to about 70,000 and optionally comprising poly-L-arginine and optionally comprising a fluorescent dye; and a fourth layer coating the third layer, the fourth layer comprising hyaluronic acid or a pharmaceutically acceptable salt thereof; and wherein the plurality of nanoparticles has an intensity-weighted average diameter as determined by dynamic light scattering from about 100 nm to about 300 nm.
  16. 16 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a nanoparticle composition of claim 15 to treat RHAMM-positive cancer in a subject.
  17. 17 . A method for treating a subject suffering from a RHAMM-positive cancer, wherein the method comprises administering to the subject an effective amount of a nanoparticle composition of claim 15 to treat the RHAMM-positive cancer.
  18. 18 . The method of claim 1 , consisting of administering to the subject an effective amount of a nanoparticle composition to treat the RHAMM-positive cancer; the nanoparticle composition comprising a plurality of nanoparticles where each nanoparticle comprises a particle core with an outer surface; a first layer coating the outer surface of the particle core, the first layer comprising poly-L-lysine with a weight-average molecular weight of about 40,000 to about 70,000 and optionally comprising poly-L-arginine and optionally comprising a fluorescent dye; a second layer coating the first layer, the second layer comprising one or more siRNA that inhibit expression of Bcl-XL, inhibit expression of MCL1, inhibit expression of Bcl-w, inhibit expression of Bcl-b, and/or inhibit expression of BFL1, wherein the siRNA has the sequence of 5′-GGUAUUGGUGAGUCGGAUCdTdT-3′ (SEQ ID NO. 2) or 5′-GAUCCGACUCACCAAUACCdTdT-3′ (SEQ ID NO. 3); a third layer coating the second layer, the third layer comprising an apoptotic peptide having the sequence of KLAKLAKKLAKLAKKLAKLAKKLAKLAK (SEQ ID NO. 1), and optionally comprising a fluorescent dye; and a fourth layer coating the third layer, the fourth layer comprising hyaluronic acid or a pharmaceutically acceptable salt thereof; and wherein the plurality of nanoparticles has an intensity-weighted average diameter as determined by dynamic light scattering from about 100 nm to about 300 nm.
  19. 19 . The nanoparticle composition of claim 5 , each nanoparticle consisting of a particle core with an outer surface; a first layer coating the outer surface of the particle core, the first layer comprising poly-L-lysine with a weight-average molecular weight of about 40,000 to about 70,000 and optionally comprising poly-L-arginine and optionally comprising a fluorescent dye; a second layer coating the first layer, the second layer comprising one or more siRNA that inhibit expression of Bcl-xL, inhibit expression of MCL1, inhibit expression of Bcl-w, inhibit expression of Bcl-b, and/or inhibit expression of BFL1, wherein the siRNA has the sequence of 5′-GGUAUUGGUGAGUCGGAUCdTdT-3′ (SEQ ID NO. 2) or 5′-GAUCCGACUCACCAAUACCdTdT-3′ (SEQ ID NO. 3); a third layer coating the second layer, the third layer comprising an apoptotic peptide having the sequence of KLAKLAKKLAKLAKKLAKLAKKLAKLAK (SEQ ID NO. 1) and optionally comprising a fluorescent dye; and a fourth layer coating the third layer, the fourth layer comprising hyaluronic acid or a pharmaceutically acceptable salt thereof; and wherein the plurality of nanoparticles has an intensity-weighted average diameter as determined by dynamic light scattering from about 100 nm to about 300 nm.
  20. 20 . The nanoparticle composition of claim 15 , each nanoparticle consisting of a particle core with an outer surface; a first layer coating the outer surface of the particle core, the first layer comprising an apoptotic peptide having the sequence of KLAKLAKKLAKLAKKLAKLAKKLAKLAK (SEQ ID NO. 1) and optionally comprising a fluorescent dye; a second layer coating the first layer, the second layer comprising one or more siRNA that inhibit expression of Bcl-XL, inhibit expression of MCL1, inhibit expression of Bcl-w, inhibit expression of Bcl-b, and/or inhibit expression of BFL1, wherein the siRNA has the sequence of 5′-GGUAUUGGUGAGUCGGAUCdTdT-3′ (SEQ ID NO. 2) or 5′-GAUCCGACUCACCAAUACCdTdT-3′ (SEQ ID NO. 3); a third layer coating the second layer, the third layer comprising poly-L-lysine with a weight-average molecular weight of about 40,000 to about 70,000 and optionally comprising poly-L-arginine and optionally comprising a fluorescent dye; and a fourth layer coating the third layer, the fourth layer comprising hyaluronic acid or a pharmaceutically acceptable salt thereof; and wherein the plurality of nanoparticles has an intensity-weighted average diameter as determined by dynamic light scattering from about 100 nm to about 300 nm.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a U.S. National Phase Application under 35 U.S.C. 371 of International Application No. PCT/US2021/028834, filed on Apr. 23, 2021, which claims the benefit of and priority to U.S. Provisional Appl. No. 63/014,508, filed Apr. 23, 2020, and the benefit of and priority to U.S. Provisional Appl. No. 63/152,536, filed Feb. 23, 2021, each of which is incorporated herein by reference in their entireties for any and all purposes. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jun. 16, 2021, is named 093873-1314 SL.txt and is 10,196 bytes in size. FIELD The present technology is directed to nanoparticle compositions and methods useful in treating RHAMM-positive cancers. SUMMARY In an aspect, a method for treating a subject suffering from a RHAMM-positive cancer is provided, where the method includes administering to the subject an effective amount of a nanoparticle composition to treat the RHAMM-positive cancer. The nanoparticle composition of the method includes a plurality of nanoparticles, where each nanoparticle includes a particle core with an outer surface; a first layer coating the outer surface of the particle core, the first layer including one or both of poly-L-lysine and poly-L-arginine and optionally including a fluorescent dye; a second layer coating the first layer, the second layer including one or more siRNA that inhibit expression of Bcl-2, inhibit expression of Bcl-xL (BCL2L1), inhibit expression of MCL1, inhibit expression of Bcl-w (BCL2L2), inhibit expression of Bcl-b (BCL2L10), and/or inhibit expression of BFL1 (BCL2A1); a third layer coating the second layer, the third layer including an apoptotic peptide and optionally including a fluorescent dye; and a fourth layer coating the third layer, the fourth layer including hyaluronic acid or a pharmaceutically acceptable salt thereof (HA); and where the plurality of nanoparticles has an intensity-weighted average diameter as determined by dynamic light scattering from about 100 nm to about 300 nm. In an aspect, a nanoparticle composition is provided that includes a plurality of nanoparticles, where each nanoparticle includes a particle core with an outer surface; a first layer coating the outer surface of the particle core, the first layer including one or both of poly-L-lysine and poly-L-arginine and optionally including a fluorescent dye; a second layer coating the first layer, the second layer including one or more siRNA that inhibit expression of Bcl-2, inhibit expression of Bcl-xL (BCL2L1), inhibit expression of MCL1, inhibit expression of Bcl-w (BCL2L2), inhibit expression of Bcl-b (BCL2L10), and/or inhibit expression of BFL1 (BCL2A1); a third layer coating the second layer, the third layer including an apoptotic peptide and optionally including a fluorescent dye; and a fourth layer coating the third layer, the fourth layer including hyaluronic acid or a pharmaceutically acceptable salt thereof (HA); and where the plurality of nanoparticles has an intensity-weighted average diameter as determined by dynamic light scattering from about 100 nm to about 300 nm. In an aspect, a method for treating a subject suffering from a RHAMM-positive cancer is provided, where the method includes administering to the subject an effective amount of a nanoparticle composition to treat the RHAMM-positive cancer, where the nanoparticle composition includes a plurality of nanoparticles, and where each nanoparticle includes a particle core with an outer surface; a first layer coating the outer surface of the particle core, the first layer including an apoptotic peptide and optionally including a fluorescent dye; a second layer coating the first layer, the second layer including one or more siRNA that inhibit expression of Bcl-2, inhibit expression of Bcl-xL (BCL2L1), inhibit expression of MCL1, inhibit expression of Bcl-w (BCL2L2), inhibit expression of Bcl-b (BCL2L10), and/or inhibit expression of BFL1 (BCL2A1); a third layer coating the second layer, the third layer including one or both of poly-L-lysine and poly-L-arginine and optionally including a fluorescent dye; and a fourth layer coating the third layer, the fourth layer including hyaluronic acid or a pharmaceutically acceptable salt thereof (HA); and where the plurality of nanoparticles has an intensity-weighted average diameter as determined by dynamic light scattering from about 100 nm to about 300 nm. In an aspect, a nanoparticle composition is provided that includes a plurality of nanoparticles, where each nanoparticle includes a particle core with an outer surface; a first layer coating the outer surface of the particle core, the first layer including an apoptotic peptide and optionally including a fluorescent dye; a second layer coating the first layer, the second layer including one