COMPOSITIONS AND METHODS FOR ORGAN SPECIFIC DELIVERY OF NUCLEIC ACIDS
The present disclosure provides compositions which shown preferential targeting or delivery of a nucleic acid composition to a particular organ. In some embodiments, the composition comprises a steroid or sterol, an ionizable cationic lipid, a phospholipid, a PEG lipid, and a permanently cationic lipid which may be used to deliver a nucleic acid.
1 . A composition comprising:
a. a chemotherapeutic agent; and
b. a lipid nanoparticle composition comprising:
(1) a selective organ targeting (SORT) compound comprising a cationic SORT lipid, an anionic SORT lipid, or a zwitterionic SORT lipid; and
(2) an ionizable cationic lipid.
2 . The composition of claim 1 , wherein said chemotherapeutic agent is present in a ratio of said lipid composition to said chemotherapeutic agent from about 1:1 to about 1:100.
3 . The composition of claim 1 , wherein said chemotherapeutic agent is configured to treat a blood cancer.
4 . The composition of claim 3 , wherein said chemotherapeutic agent is configured to treat Hodgkin lymphoma.
5 . The composition of claim 4 , wherein said chemotherapeutic agent is Doxorubicin Hydrochloride.
6 . The composition of claim 4 , wherein said chemotherapeutic agent is Keytruda (Pembrolizumab).
7 . The composition of claim 4 , wherein said chemotherapeutic agent is Opdivo (Nivolumab).
8 . The composition of claim 3 , wherein said chemotherapeutic agent is configured to treat leukemia.
9 . The composition of claim 8 , wherein said chemotherapeutic agent is Dasatinib.
10 . The composition of claim 8 , wherein said chemotherapeutic agent is Doxorubicin Hydrochloride.
11 . The composition of claim 8 , wherein said chemotherapeutic agent is Pemazyre (Pemigatinib).
12 . The composition of claim 3 , wherein said chemotherapeutic agent is configured to treat multiple myeloma or other plasma cell neoplasms.
13 . The composition of claim 12 , wherein said chemotherapeutic agent is abecma (idecabtagene vicleucel).
14 . The composition of claim 12 , wherein said chemotherapeutic agent is doxil (doxorubicin hydrochloride liposome).
15 . The composition of claim 12 , wherein said chemotherapeutic agent is doxorubicin hydrochloride.
16 . The composition of claim 12 , wherein said chemotherapeutic agent is elotuzumab.
17 . The composition of claim 3 , wherein said chemotherapeutic agent is configured to treat myeloproliferative neoplasms.
18 . The composition of claim 17 , wherein said chemotherapeutic agent is doxorubicin hydrochloride.
19 . The composition of claim 17 , wherein said chemotherapeutic agent is gleevec (imatinib mesylate).
20 . The composition of claim 17 , wherein said chemotherapeutic agent is pemigatinib.
21 . The composition of claim 3 , wherein said chemotherapeutic agent is configured to treat non-Hodgkin lymphoma.
22 . The composition of claim 21 , wherein said chemotherapeutic agent is bicnu (carmustine).
23 . The composition of claim 21 , wherein said chemotherapeutic agent is doxorubicin hydrochloride.
24 . The composition of claim 21 , wherein said chemotherapeutic agent is pembrolizumab.
25 . The composition of claim 1 , wherein said chemotherapeutic agent is configured to treat a solid tumor.
26 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat bone cancer.
27 . The composition of claim 26 , wherein said chemotherapeutic agent is Doxorubicin Hydrochloride.
28 . The composition of claim 26 , wherein said chemotherapeutic agent is Methotrexate Sodium.
29 . The composition of claim 26 , wherein said chemotherapeutic agent is Xgeva (Denosumab).
30 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat brain tumors.
31 . The composition of claim 30 , wherein said chemotherapeutic agent is BiCNU (Carmustine).
32 . The composition of claim 30 , wherein said chemotherapeutic agent is Mvasi (Bevacizumab).
33 . The composition of claim 30 , wherein said chemotherapeutic agent is Welireg (Belzutifan).
34 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat breast cancer.
35 . The composition of claim 34 , wherein said chemotherapeutic agent is Doxorubicin Hydrochloride.
36 . The composition of claim 34 , wherein said chemotherapeutic agent is Keytruda (Pembrolizumab).
37 . The composition of claim 34 , wherein said chemotherapeutic agent is Paclitaxel.
38 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat cervical cancer.
39 . The composition of claim 38 , wherein said chemotherapeutic agent is Bevacizumab.
40 . The composition of claim 38 , wherein said chemotherapeutic agent is Keytruda (Pembrolizumab).
41 . The composition of claim 38 , wherein said chemotherapeutic agent is Topotecan Hydrochloride.
42 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat colon or rectal cancer.
43 . The composition of claim 42 , wherein said chemotherapeutic agent is Bevacizumab.
44 . The composition of claim 42 , wherein said chemotherapeutic agent is Cetuximab.
45 . The composition of claim 42 , wherein said chemotherapeutic agent is Keytruda (Pembrolizumab).
46 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat endometrial cancer.
47 . The composition of claim 46 , wherein said chemotherapeutic agent is Dostarlimab-gxly.
48 . The composition of claim 46 , wherein said chemotherapeutic agent is Lenvatinib Mesylate.
49 . The composition of claim 46 , wherein said chemotherapeutic agent is Pembrolizumab.
50 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat esophageal cancer.
51 . The composition of claim 50 , wherein said chemotherapeutic agent is Keytruda (Pembrolizumab).
52 . The composition of claim 50 , wherein said chemotherapeutic agent is Docetaxel.
53 . The composition of claim 50 , wherein said chemotherapeutic agent is Ramucirumab.
54 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat gastrointestinal stromal tumors.
55 . The composition of claim 54 , wherein said chemotherapeutic agent is Imatinib Mesylate.
56 . The composition of claim 54 , wherein said chemotherapeutic agent is Regorafenib.
57 . The composition of claim 54 , wherein said chemotherapeutic agent is Sunitinib Malate.
58 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat gestational trophoblastic disease.
59 . The composition of claim 58 , wherein said chemotherapeutic agent is Dactinomycin.
60 . The composition of claim 58 , wherein said chemotherapeutic agent is Methotrexate Sodium.
61 . The composition of claim 58 , wherein said chemotherapeutic agent is Vinblastine Sulfate.
62 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat head or neck cancer.
63 . The composition of claim 62 , wherein said chemotherapeutic agent is Bleomycin Sulfate.
64 . The composition of claim 62 , wherein said chemotherapeutic agent is Keytruda (Pembrolizumab).
65 . The composition of claim 62 , wherein said chemotherapeutic agent is Methotrexate Sodium.
66 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat Kaposi sarcoma.
67 . The composition of claim 66 , wherein said chemotherapeutic agent is Doxorubicin Hydrochloride Liposome.
68 . The composition of claim 66 , wherein said chemotherapeutic agent is Paclitaxel.
69 . The composition of claim 66 , wherein said chemotherapeutic agent is Vinblastine Sulfate.
70 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat kidney cancer.
71 . The composition of claim 70 , wherein said chemotherapeutic agent is Avastin (Bevacizumab).
72 . The composition of claim 70 , wherein said chemotherapeutic agent is Avelumab.
73 . The composition of claim 70 , wherein said chemotherapeutic agent is Pembrolizumab.
74 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat liver cancer.
75 . The composition of claim 74 , wherein said chemotherapeutic agent is Atezolizumab.
76 . The composition of claim 74 , wherein said chemotherapeutic agent is Avastin (Bevacizumab).
77 . The composition of claim 74 , wherein said chemotherapeutic agent is Keytruda (Pembrolizumab).
78 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat lung cancer.
79 . The composition of claim 78 , wherein said chemotherapeutic agent is Afinitor (Everolimus).
80 . The composition of claim 78 , wherein said chemotherapeutic agent is Atezolizumab.
81 . The composition of claim 78 , wherein said chemotherapeutic agent is Doxorubicin Hydrochloride.
82 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat malignant mesothelioma.
83 . The composition of claim 82 , wherein said chemotherapeutic agent is Ipilimumab.
84 . The composition of claim 82 , wherein said chemotherapeutic agent is Nivolumab.
85 . The composition of claim 82 , wherein said chemotherapeutic agent is Yervoy (Ipilimumab).
86 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat melanoma.
87 . The composition of claim 86 , wherein said chemotherapeutic agent is Dabrafenib Mesylate.
88 . The composition of claim 86 , wherein said chemotherapeutic agent is Ipilimumab.
89 . The composition of claim 86 , wherein said chemotherapeutic agent is Pembrolizumab.
90 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat Multicentric Castleman Disease.
91 . The composition of claim 90 , wherein said chemotherapeutic agent is Siltuximab.
92 . The composition of claim 90 , wherein said chemotherapeutic agent is Sylvant (Siltuximab).
93 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat neuroblastoma.
94 . The composition of claim 93 , wherein said chemotherapeutic agent is Cyclophosphamide.
95 . The composition of claim 93 , wherein said chemotherapeutic agent is Doxorubicin Hydrochloride.
96 . The composition of claim 93 , wherein said chemotherapeutic agent is Vincristine Sulfate.
97 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat ovarian, fallopian tube, or primary peritoneal cancer.
98 . The composition of claim 97 , wherein said chemotherapeutic agent is Bevacizumab.
99 . The composition of claim 97 , wherein said chemotherapeutic agent is Cisplatin.
100 . The composition of claim 97 , wherein said chemotherapeutic agent is Doxorubicin Hydrochloride.
101 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat pancreatic cancer.
102 . The composition of claim 101 , wherein said chemotherapeutic agent is Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation).
103 . The composition of claim 101 , wherein said chemotherapeutic agent is Gemcitabine Hydrochloride.
104 . The composition of claim 101 , wherein said chemotherapeutic agent is Tarceva (Erlotinib Hydrochloride).
105 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat penile cancer.
106 . The composition of claim 105 , wherein said chemotherapeutic agent is Bleomycin Sulfate.
107 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat pheochromocytoma or paraganglioma.
108 . The composition of claim 107 , wherein said chemotherapeutic agent is Azedra (Iobenguane 1131).
109 . The composition of claim 107 , wherein said chemotherapeutic agent is Hemangeol (Propranolol Hydrochloride).
110 . The composition of claim 107 , wherein said chemotherapeutic agent is Iobenguane 1131.
111 . The composition of claim 107 , wherein said chemotherapeutic agent is Propranolol Hydrochloride.
112 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat prostate cancer.
113 . The composition of claim 112 , wherein said chemotherapeutic agent is Docetaxel.
114 . The composition of claim 112 , wherein said chemotherapeutic agent is Eligard (Leuprolide Acetate).
115 . The composition of claim 112 , wherein said chemotherapeutic agent is Rucaparib Camsylate.
116 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat retinoblastoma.
117 . The composition of claim 116 , wherein said chemotherapeutic agent is Cyclophosphamide.
118 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat rhabdomyosarcoma.
119 . The composition of claim 118 , wherein said chemotherapeutic agent is Cosmegen (Dactinomycin).
120 . The composition of claim 118 , wherein said chemotherapeutic agent is Dactinomycin.
121 . The composition of claim 118 , wherein said chemotherapeutic agent is Vincristine Sulfate.
122 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat skin cancer.
123 . The composition of claim 122 , wherein said chemotherapeutic agent is Pembrolizumab.
124 . The composition of claim 122 , wherein said chemotherapeutic agent is Imlygic (Talimogene Laherparepvec).
125 . The composition of claim 122 , wherein said chemotherapeutic agent is Nivolumab.
126 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat soft tissue sarcoma.
127 . The composition of claim 126 , wherein said chemotherapeutic agent is Dactinomycin.
128 . The composition of claim 126 , wherein said chemotherapeutic agent is Doxorubicin Hydrochloride.
129 . The composition of claim 126 , wherein said chemotherapeutic agent is Imatinib Mesylate.
130 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat solid tumors anywhere in the body.
131 . The composition of claim 130 , wherein said chemotherapeutic agent is Pembrolizumab.
132 . The composition of claim 130 , wherein said chemotherapeutic agent is Selpercatinib.
133 . The composition of claim 130 , wherein said chemotherapeutic agent is Trametinib Dimethyl Sulfoxide.
134 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat stomach (gastric) cancer.
135 . The composition of claim 134 , wherein said chemotherapeutic agent is Doxorubicin Hydrochloride.
136 . The composition of claim 134 , wherein said chemotherapeutic agent is Keytruda (Pembrolizumab).
137 . The composition of claim 134 , wherein said chemotherapeutic agent is Trastuzumab.
138 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat testicular cancer.
139 . The composition of claim 138 , wherein said chemotherapeutic agent is Bleomycin Sulfate.
140 . The composition of claim 138 , wherein said chemotherapeutic agent is Cisplatin.
141 . The composition of claim 138 , wherein said chemotherapeutic agent is Vinblastine Sulfate.
142 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat thyroid cancer.
143 . The composition of claim 142 , wherein said chemotherapeutic agent is Doxorubicin Hydrochloride.
144 . The composition of claim 142 , wherein said chemotherapeutic agent is Gavreto (Pralsetinib).
145 . The composition of claim 142 , wherein said chemotherapeutic agent is Tafinlar (Dabrafenib Mesylate).
146 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat vaginal cancer.
147 . The composition of claim 25 , wherein said chemotherapeutic agent is configured to treat vulvar cancer.
148 . The composition of claim 147 , wherein said chemotherapeutic agent is Bleomycin Sulfate.
149 . The composition of claim 1 , wherein the composition for use according to claim 1 , wherein a surface of said lipid nanoparticle composition binds to apolipoprotein E (Apo E) to vitronectin or apolipoprotein H (Apo H) as determined by a quantitative mass spectroscopy.
150 . The composition of claim 1 , wherein the target organ is selected from lungs, lymph nodes, and the spleen.
151 . The composition of claim 150 , wherein the target organ is the lungs.
152 . The composition of claim 150 , wherein the target organ is the spleen.
153 . The composition for use of claim 1 , wherein the lipid nanoparticle composition is characterized by one or more of the following:
(i) the ionizable cationic lipid is present in the lipid nanoparticle composition at a molar percentage from about 5% to about 30%;
(ii) the phospholipid is present in the lipid nanoparticle composition at a molar percentage from about 8% to about 20% or from about 20% to about 23%;
(iii) a steroid is present in the lipid nanoparticle composition, optionally, at a molar percentage from about 15% to about 39%, or from about 39% to about 46%; or/and
(iv) a polyethylene glycol-conjugated (PEGylated) lipid is present in the lipid nanoparticle composition, optionally, at a molar percentage from about 0.5% to about 10.0%.
154 . The composition for use of claim 1 , wherein therapeutic agent comprises a nucleic acid selected from a short interfering ribonucleic acid (siRNA), a micro-ribonucleic acid (miRNA), a pri-miRNA, a messenger RNA (mRNA), a clustered regularly interspaced short palindromic repeats (CRISPR) related nucleic acid, a single guide RNA (sgRNA), a CRISPR-RNA (crRNA), a trans-activating crRNA (tracrRNA), a plasmid DNA (pDNA), a transfer RNA (tRNA), an antisense oligonucleotide (ASO), a guide RNA, a double stranded DNA (dsDNA), a single stranded DNA (ssDNA), a single stranded RNA (ssRNA), and a double stranded RNA (dsRNA); optionally, wherein the nucleic acid is present in the lipid nanoparticle composition at a ratio from about 1:1 to about 1:100.
155 . The composition for use of claim 1 , wherein the use comprises intravenously administering the composition to a subject.
156 . The composition for use of claim 1 , wherein said lipid nanoparticle composition comprises a plurality of lipid nanoparticle.
157 . The composition of claim 1 , wherein said composition delivers a greater amount or provides a greater amount of activity of said chemotherapeutic agent in said non-liver organ or said non-liver cell in said subject as compared to that achieved absent said SORT compound.
158 . The composition of claim 1 , wherein said cationic SORT lipid is a permanently cationic lipid, optionally, a permanently cationic lipid comprising a quaternary ammonium ion.
159 . The composition of claim 1 , wherein said SORT compound has a structural formula of Formula (I A ), (II A ), or (III A ):
wherein, in Formula (I A ):
R 1 and R 2 are each independently optionally substituted alkyl (C8-C24) , or optionally substituted alkenyl (C8-C24) ;
R 3 , R 3 ′, and R 3 ″ are each independently optionally substituted alkyl (C≤6) ; and
X − is a monovalent anion; or
wherein, in Formula (II A ):
R 4 and R 4 ′ are each independently optionally substituted alkyl (C6-C24) , or optionally substituted alkenyl (C6-C24) ;
R 4 ″ is optionally substituted alkyl (C≤24) , or optionally substituted alkenyl (C≤24) ;
R 4 ′″ is optionally substituted alkyl (C1-C8) , or optionally substituted alkenyl (C2-C8) ; and
X 2 is a monovalent anion; or
wherein, in Formula (III A ):
R 1 and R 2 are each independently optionally substituted alkyl (C8-C24) , or optionally substituted alkenyl (C8-C24) ;
R 3 , R 3 ′, and R 3 ″ are each independently optionally substituted alkyl (C≤6) ;
R 4 is optionally substituted alkyl (C≤6) ; and
X − is a monovalent anion;
for example, the permanently cationic lipid is selected from:
160 . The composition of claim 1 , wherein said cationic SORT lipid is present in the lipid nanoparticle composition at a molar percentage from about 5% to about 20% or from about 20% to about 65%.
161 . The composition of claim 1 , wherein said anionic SORT lipid is a permanently anionic lipid, for example, a permanently anionic lipid comprising a phosphate group.
162 . The composition of claim 1 , wherein said SORT compound has a structural formula of Formula (IV A ):
wherein, in Formula (IV A ):
R 1 and R 2 are each independently optionally substituted alkyl (C8-C24) , or optionally substituted alkenyl (C8-C24) ; and
R 3 is hydrogen, or optionally substituted alkyl (C≤6) , or —Y 1 —R 4 , wherein:
Y 1 is optionally substituted alkanediyl (C≤6) ; and
R 4 is optionally substituted acyloxy (C≤8-24) ;
for example, the permanently anionic lipid is:
163 . The composition of claim 1 , wherein said anionic SORT lipid is present in the lipid nanoparticle composition at a molar percentage from about 5% to about 50%.
164 . The composition of claim 1 , wherein said SORT compound is a C 6 -C 24 diacyl phosphotidylcholine, optionally, having the structural formula;
wherein, in Formula (V A ):
R 1 and R 2 are each independently optionally substituted alkyl (C8-C24) , or optionally substituted alkenyl (C8-C24) ;
R 3 , R 3 ′, and R 3 ″ are each independently optionally substituted alkyl (C≤6) or optionally substituted alkyl (C≤6) ; and
X − is a monovalent anion;
for example, the SORT compound is:
165 . The composition of claim 164 , wherein said diacyl phosphotidylcholine is present in the lipid nanoparticle composition at a molar percentage from about 5% to about 50%.