CN116456967A - 可离子化脂质体、其制备及在基因递送中的应用 - Google Patents
可离子化脂质体、其制备及在基因递送中的应用 Download PDFInfo
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- NNBZCPXTIHJBJL-UHFFFAOYSA-N trans-decahydronaphthalene Natural products C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 1
- NNBZCPXTIHJBJL-MGCOHNPYSA-N trans-decalin Chemical compound C1CCC[C@@H]2CCCC[C@H]21 NNBZCPXTIHJBJL-MGCOHNPYSA-N 0.000 description 1
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- 125000002469 tricosyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005040 tridecenyl group Chemical group C(=CCCCCCCCCCCC)* 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
- C12N15/88—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using amphiphile liposome vesicle
Abstract
Description
样品编号 | 粒径 | PDI | 包封率 | 细胞活率 | 阳性率 | 荧光强度 |
A-C12 | 91.6 | 0.173 | 89.80% | 87.1% | 73.3% | 0.84 |
A-C14 | 97.1 | 0.107 | 80.31% | 95.4 | 92.3% | 0.30 |
A-C16 | 90.8 | 0.183 | 90.30% | 90.0% | 66.3% | 0.80 |
A-C18 | 96.9 | 0.144 | 90.56% | 93.0% | 61.9% | 0.87 |
B-C12 | 102.9 | 0.147 | 89.93% | 85.0% | 83.0% | 0.20 |
B-C14 | 90.5 | 0.133 | 95.21% | 95.0% | 90.2% | 1.00 |
B-C16 | 101.7 | 0.071 | 85.25% | 90.2% | 65.7% | 0.49 |
B-C18 | 108.3 | 0.118 | 94.79% | 89.6% | 68.6% | 0.27 |
C-C12 | 92.5 | 0.070 | 95.24% | 94.0% | 64.4% | 0.71 |
C-C14 | 92.2 | 0.171 | 92.82% | 94.6 | 93.6% | 0.75 |
C-C16 | 94.1 | 0.108 | 90.26% | 97.6% | 85.2% | 0.87 |
C-C18 | 107.6 | 0.134 | 81.92% | 89.6% | 86.1% | 0.74 |
D-C12 | 90.5 | 0.073 | 91.80% | 90.8% | 65.6% | 0.07 |
D-C14 | 97.2 | 0.168 | 92.36% | 91.3 | 96.7% | 0.95 |
D-C16 | 91.6 | 0.117 | 86.56% | 91.1% | 71.7% | 0.82 |
D-C18 | 103.0 | 0.105 | 88.54% | 81.5% | 64.4% | 0.45 |
E-C12 | 96.9 | 0.133 | 95.02% | 84.8% | 56.4% | 0.69 |
E-C14 | 85.2 | 0.119 | 85.62% | >99.0 | 84.3% | 0.45 |
E-C16 | 76.9 | 0.107 | 91.51% | 94.4% | 59.9% | 0.71 |
E-C18 | 84.5 | 0.136 | 92.86% | 98.5% | 65.2% | 0.14 |
F-C12 | 77.7 | 0.133 | 92.31% | 87.1% | 63.9% | 0.28 |
F-C14 | 82.4 | 0.131 | 95.21% | 93.2 | 73.5% | 0.33 |
F-C16 | 91.9 | 0.099 | 92.39% | 96.8% | 60.3% | 0.17 |
F-C18 | 77.2 | 0.081 | 80.61% | 93.5% | 61.5% | 0.67 |
G-C12 | 89.3 | 0.172 | 89.95% | 92.9% | 83.1% | 0.29 |
G-C14 | 86.4 | 0.180 | 84.02% | >99.0% | 67.5 | 0.30 |
G-C16 | 78.2 | 0.102 | 85.40% | 94.5% | 79.6% | 0.54 |
G-C18 | 99.8 | 0.195 | 80.79% | 95.2% | 63.9% | 0.63 |
H-C12 | 95.9 | 0.136 | 94.13% | 86.0% | 74.3% | 0.78 |
H-C14 | 94.8 | 0.099 | 91.67% | 91.7% | 66.8% | 0.52 |
H-C16 | 95.5 | 0.162 | 86.56% | >99.0% | 59.0% | 0.77 |
H-C18 | 73.8 | 0.143 | 80.61% | 97.4% | 81.9% | 0.38 |
I-C12 | 83.8 | 0.114 | 88.38% | 98.5% | 63.9% | 0.05 |
I-C14 | 120.3 | 0.180 | 87.59% | 97.0% | 62.7% | 0.05 |
I-C16 | 96.3 | 0.147 | 91.60% | 81.3% | 68.7% | 0.06 |
I-C18 | 72.3 | 0.109 | 83.06% | 86.0% | 66.4% | 0.04 |
J-C12 | 99.7 | 0.105 | 92.88% | 81.8% | 62.6% | 0.04 |
J-C14 | 126.1 | 0.121 | 83.58% | >99.0% | 59.1% | 0.06 |
J-C16 | 104.1 | 0.077 | 81.08% | 85.2% | 62.0% | 0.04 |
J-C18 | 93.7 | 0.163 | 88.56% | 83.6% | 60.9% | 0.04 |
K-C12 | 75.9 | 0.075 | 92.83% | >99.0% | 62.8% | 0.07 |
K-C14 | 122.7 | 0.155 | 87.00% | 82.3% | 59.8% | 0.03 |
K-C16 | 76.0 | 0.185 | 95.74% | 93.4% | 60.2% | 0.04 |
K-C18 | 124.2 | 0.134 | 92.77% | >99.0% | 74.7% | 0.05 |
L-C12 | 88.4 | 0.181 | 93.38% | 84.9% | 58.1% | 0.07 |
L-C14 | 101.5 | 0.126 | 91.54% | 99.0% | 60.0% | 0.04 |
L-C16 | 111.5 | 0.085 | 92.34% | 97.2% | 64.8% | 0.06 |
L-C18 | 124.0 | 0.182 | 91.70% | 98.6% | 59.7% | 0.02 |
Claims (15)
- 下式I所示的可电离脂质化合物,其立体异构体、互变异构体、药学上可接受的盐、前药或溶剂合物:式中,A 1和A 2各自独立为CH或N;B选自-L 4-N(R 9R 10)或R 12;L 1、L 2、L 3和L 4各自独立选自任选取代的亚烷基、任选取代的-[(CH 2) nO] m-(CH 2) o-、任选取代的亚链烯基和任选取代的亚炔基;R 1、R 2、R 3、R 4、R 9、R 10和R 12各自独立为H、卤素、任选取代的烷基、任选取代的链烯基、任选取代的环烷基、任选取代的杂环基、任选取代的环烯基、任选取代的环炔基、任选取代的芳基、任选取代的杂芳基、任选取代的烷氧基任选取代的烷氧基羰基、任选取代的酰基、-NR’R”、羧基、硝基、氰基或烷基亚砜基;R 5a、R 5b、R 6a、R 6b、R 7a、R 7b、R 8a和R 8b各自独立选自H、任选取代的烷基、任选取代的链烯基、任选取代的炔基、卤素、硝基、氰基、-NR’R”和羧基;n、m和o各自独立为1-10的整数;和R’和R”各自独立选自H或任选取代的烷基。
- 如权利要求1所述的可电离脂质化合物或其立体异构体、互变异构体、药学上可接受的盐、前药或溶剂合物,其特征在于,A 1和A 2都是N;和/或L 1、L 2、L 3和L 4各自独立为任选被选自羟基、-NR’R”、C 1-4烷氧基和卤素的1-5个取代基取代的C1-4亚烷基或-[(CH 2) nO] m-(CH 2) o-,其中,R’和R”各自独立选自H和C 1-4烷基;更优选地,L 1、L 2、L 3和L 4各自独立为C 1-4亚烷基或-[(CH 2) nO] m-(CH 2) o-;优选地,n、m和o各自独立为1-4的整数;更优选地,n为2,m为1-4, o为2;更优选地,L 1、L 2、L 3和L 4都为C 1-4亚烷基,或L 1、L 2和L 4各自独立为-[(CH 2) nO] m-(CH 2) o-,优选地,L 1、L 2和L 4为相同的基团,L 3为C 1-4亚烷基;和/或R 5a、R 5b、R 6a、R 6b、R 7a、R 7b、R 8a和R 8b各自独立选自H和任选被1-5个选自羟基和卤素的取代基取代的C 1-4烷基;优选地,R 5a、R 5b、R 6a、R 6b、R 7a、R 7b、R 8a和R 8b均为H。
- 如权利要求1-2中任一项所述的可电离脂质化合物或其立体异构体、互变异构体、药学上可接受的盐、前药或溶剂合物,其特征在于,R 1、R 2、R 3和R 4各自独立为被羟基和/或卤素取代的C 1-24烷基,优选各自独立为被羟基和/或卤素取代的C 8-24烷基;优选地,该烷基连接所述N原子端的第2个碳原子被1个羟基取代;优选地R 1、R 2、R 3和R 4各自独立为-CH 2CH(OH)CH 2R 11,其中,所述R 11为未取代的或卤素取代的C 1-21烷基,优选为未取代的或全氟取代的C 1-21烷基;优选地,R 1、R 2、R 3和R 4为相同的基团;和/或R 9、R 10和R 12各自独立为任选地被羟基和/或卤素取代的C 1-24烷基,优选各自独立为任选地被羟基和/或卤素取代的C 8-24烷基;优选地,该烷基连接所述N原子端的第2个碳原子被1个羟基取代;优选地,R 9和R 10各自独立为-CH 2CH(OH)CH 2R 11,其中,所述R 11为未取代或卤素取代的C 1-21烷基,优选为未取代或全氟取代的C 1-21烷基;优选地,R 9和R 10均为所述-CH 2CH(OH)CH 2R 11基团;优选地,R 12为任选地被1-5个羟基取代的C 1-10烷基,优选地,该烷基的与N连接端的第2个碳原子被羟基取代;更优选地,R 1、R 2、R 3、R 4、R 9和R 10为相同的基团。
- 如权利要求1所述的可电离脂质化合物或其立体异构体、互变异构体、药学上可接受的盐、前药或溶剂合物,其特征在于,A 1和A 2都是N;R 1、R 2、R 3和R 4各自独立为任选地被羟基和/或卤素取代的C 1-24烷基;优选地,R 1、R 2、R 3和R 4至少被1个羟基取代;优选地,R 1、R 2、R 3和R 4各自独立为-CH 2CH(OH)CH 2R 11,其中,所述R 11为任选地被卤素取代的C 1-21烷基,优选R 11为未取代的C 1-21烷基或全氟取代的C 1-21烷基;R 5a、R 5b、R 6a、R 6b、R 7a、R 7b、R 8a和R 8b均为H;B为-L 4-N(R 9R 10);其中,L 1、L 2、L 3和L 4都为C 1-4亚烷基,优选地,L 1、L 2、L 3和L 4为相同的亚烷基;或L 1、L 2和L 4各自独立为-[(CH 2) nO] m-(CH 2) o-,优选地,L 1、L 2和L 4为相同的基团,L 3为C 1-4亚烷基;R 9和R 10各自独立为任选地被羟基和/ 或卤素取代的C 1-24烷基;优选地,R 9和R 10至少被1个羟基取代;优选地,R 9和R 10各自独立为-CH 2CH(OH)CH 2R 11,其中,所述R 11为任选地被卤素取代的C 1-21烷基,优选地,R 11为未取代的C 1-21烷基或全氟取代的C 1-21烷基;或B为R 12;其中,R 12为任选地被1-5个羟基取代的C 1-10烷基,优选地,该烷基的与N连接端的第2个碳原子被羟基取代;L 1和L 2各自独立为-[(CH 2) nO] m-(CH 2) o-或C 1-4亚烷基,优选地,L 1与L 2为相同的基团;L 3为C 1-4亚烷基;n、m和o各自独立为1-4的整数。
- 如权利要求1所述的可电离脂质化合物或其立体异构体、互变异构体、药学上可接受的盐、前药或溶剂合物,其特征在于,所述式I化合物具有如下结构:各式中,a、b、c、d、e和f各自独立为0至20的整数,优选为8至16的整数,优选地,a、b、c、d、e和f均为0至20的同一整数,优选为8至16的同一整数。
- 如权利要求1所述的可电离脂质化合物或其立体异构体、互变异构体、药学上可接受的盐、前药或溶剂合物,其特征在于,所述式I化合物选自化合物A-C12、 A-C14、A-C16、A-C18、B-C12、B-C14、B-C16、B-C18、C-C12、C-C14、C-C16、C-C18、D-C12、D-C14、D-C16、D-C18、E-C12、E-C14、E-C16、E-C18、F-C12、F-C14、F-C16、F-C18、G-C12、G-C14、G-C16、G-C18、H-C12、H-C14、H-C16、H-C18、I-C12、I-C14、I-C16、I-C18、J-C12、J-C14、J-C16、J-C18、K-C12、K-C14、K-C16、K-C18、L-C12、L-C14、L-C16和L-C18。
- 一种脂质纳米颗粒,其含有权利要求1-6中任一项所述的可电离脂质化合物或其立体异构体、互变异构体、药学上可接受的盐、前药或溶剂合物;优选地,所述脂质纳米颗粒还含有:一种或多种辅助脂质分子、一种或多种胆固醇或胆固醇衍生物和/或一种或多种聚合物缀合的脂质分子。
- 如权利要求7所述的脂质纳米颗粒,其特征在于:所述辅助脂质分子为中性脂质分子,优选选自:DSPC、DPPC、DMPC、DOPC、POPC、DOPE和SM,更优选为DOPE或DSPC;和/或所述聚合物缀合的脂质分子中,所述聚合物为聚乙二醇;优选地,所述聚合物缀合的脂质分子选自PEG-DAG、PEG-PE、PEG-S-DAG、PEG-DSPE、PEG-cer、DMG-PEG和PEG二烷氧基丙基氨基甲酸酯,优选为PEG2000-DSPE或DMG-PEG2000。
- 如权利要求7-8中任一项所述的脂质纳米颗粒,其特征在于,所述脂质体纳米颗粒中,所述可电离脂质化合物或其立体异构体、互变异构体、药学上可接受的盐、前药或溶剂合物与辅助脂质分子、胆固醇或胆固醇衍生物、聚合物缀合的脂质分子的摩尔比为60~5∶60~5∶50~5∶10~1,优选为40~10∶30~10∶50~20∶8~1。
- 如权利要求7-9中任一项所述的脂质纳米颗粒,其特征在于,所述脂质纳米颗粒用于表达由mRNA编码的蛋白质,其中,所述蛋白质为具有治疗、预防或改善生物体生理机能的蛋白质,包括抗原和抗体;或所述脂质纳米颗粒用于通过递送靶向特定miRNA的miRNA抑制剂或者调节一种靶mRNA或几种mRNA的一组miRNA来上调内源性蛋白表达;或所述脂质纳米颗粒用于下调靶基因的蛋白质水平和/或mRNA水平;或所述脂质纳米颗粒用于递送mRNA和质粒以表达转基因;或所述脂质纳米颗粒用于诱导由蛋白质表达产生的药理学效应。
- 如权利要求7-10中任一项所述的脂质纳米颗粒,其特征在于,所述脂质纳米颗粒还含有治疗剂或活性剂;优选地,所述治疗剂或活性剂为核酸类治疗剂或活性剂;更优选地,所述核酸类治疗剂或活性剂选自:信使RNA(mRNA)、反义寡核苷酸(ASO)、小干扰RNA(siRNA)、微小RNA(miRNA)、核酶和适体。
- 一种组合物,其含有权利要求1-6中任一项所述的可电离脂质化合物或其立体异构体、互变异构体、药学上可接受的盐、前药或溶剂合物;优选地,所述组合物是药物组合物,其含有权利要求1-6中任一项所述的可电离脂质化合物或其立体异构体、互变异构体、药学上可接受的盐、前药或溶剂合物,治疗剂或活性剂,以及一种或多种辅助脂质分子、一种或多种胆固醇或胆固醇衍生物和/或一种或多种聚合物缀合的脂质分子。
- 如权利要求12所述的组合物,其特征在于,所述辅助脂质分子为中性脂质分子,优选选自:DSPC、DPPC、DMPC、DOPC、POPC、DOPE和SM,更优选为DOPE;和/或所述聚合物缀合的脂质分子中,所述聚合物为聚乙二醇;优选地,所述聚合物缀合的脂质分子选自PEG-DAG、PEG-PE、PEG-S-DAG、PEG-DSPE、PEG-cer和PEG二烷氧基丙基氨基甲酸酯,优选为PEG2000-DSPE;和/或所述治疗剂或活性剂为核酸类治疗剂或活性剂;优选地,所述核酸类治疗剂或活性剂选自:信使RNA(mRNA)、反义寡核苷酸(ASO)、小干扰RNA(siRNA)、微小RNA(miRNA)、核酶和适体。
- 如权利要求12或13所述的组合物,其特征在于,所述组合物还含有载脂蛋白;优选地,所述载脂蛋白选自:ApoA-I、ApoA-II、ApoA-IV、ApoA-V和ApoE,以及它们的活性多晶型物、同工型、变体和突变体及其片段或截短形式,优选为ApoE4。
- 权利要求1-6中任一项所述的可电离脂质化合物或其立体异构体、互变异构体、药学上可接受的盐、前药或溶剂合物在制备用于治疗或预防对象的疾病或病症的脂质纳米颗粒或药物组合物中的应用,或在制备用于递送治疗剂或活性剂如核酸分子的试剂中的应用。
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