CN103405774A - Novel drug targeting delivery adjuvant - Google Patents
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- CN103405774A CN103405774A CN201210408148XA CN201210408148A CN103405774A CN 103405774 A CN103405774 A CN 103405774A CN 201210408148X A CN201210408148X A CN 201210408148XA CN 201210408148 A CN201210408148 A CN 201210408148A CN 103405774 A CN103405774 A CN 103405774A
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Abstract
The invention provides a novel drug targeting delivery adjuvant which is at least one of pentose, hexose, sugar alcohol and disaccharide, wherein the pentose is selected from at least one of xylose and arabinose; the hexose is selected from at least one of glucose, galactose, fructose and mannose; the disaccharide is selected from at least one of sucrose, lactose, maltose and mycose; the sugar alcohol is selected from at least one of sorbitol, mannitol, erythritol, maltitol, lactitol and xylitol. Furthermore, the invention provides an application of the novel drug targeting delivery adjuvant in drug delivery, especially in targeting delivery of antisense oligodeoxynucleotide drugs PMO, PNA, 2'ome RNA (Ribonucleic Acid), peptide-PMO and siRNAs as well as macromolecular plasmids. The adjuvant has a good targeting delivery effect, and is capable of remarkably enhancing the acting effect of a drug in a target tissue; the adjuvant, which is extracted from natural products, namely saccharides, is high in clinical safety index, basically free from hurt to human body, and low in or free from toxic and side effects.
Description
Technical field
The invention belongs to life sciences and pharmaceutical carrier field.
Background technology
The targeting conevying efficiency of medicine is the key factor that determines medicine effect, and the method that is commonly used to now the optimized gene medicine has: this body structure of medicine is optimized; Use macromolecule polyalcohol as transport agent, wherein modal is exactly nano material; Organize the use of targeting peptides, be about to peptide section and medicine covalent bond.
Being most widely used of pharmaceutical carrier wherein, but the weak point that existing medicament transport carrier exists is:
1, the targeting conevying efficiency is low;
2, human body is existed to potential harm.
The Du Xing muscular dystrophy of take is example, and the Du Xing muscular dystrophy is a kind of and the lethal neuromuscular deficiency disorder heredity of mankind's X-linkage, and the sickness rate in newborn boy is 1: 3500, and cardinal symptom shows as whole-body muscle and continues to consume and degenerate.If treatment not in time, the life-span of most patient only, about 20 years old, is seriously endangered people's health.
The pathogenetic reason of disease is that the DMD gene of encoding dystrophin dystrophin is undergone mutation, and causes the splicing change of corresponding mRNA precursor and the destruction of reading frame, due to the dystrophin albumen of the biological function of can not encoding.The DMD gene is one of gene maximum in human genome, and total length is 2.4Mbp, is comprised of 79 exons, and therefore except from parent's heredity, DMD gene itself also exists very high spontaneous mutation probability.In the sudden change of DMD gene, wherein 65% sudden change is deletion mutation, other mutation type be repeat to suddenly change, the restructuring of point mutation and mini-gene fragment, these sudden changes finally all can cause the change of DMD gene code reading frame, thereby produce the dystrophin albumen unstable, that nonfunctional is active.The disappearance of dystrophin albumen can cause the unstable of meat fiber film and extracellular Ca
2+Pour in, and to the hypofunction of external force injury repairing, thereby cause muscle deterioration and atrophy consumption, show as clinically serious Du Xing muscular dystrophy.
The dystrophin albumen of DMD gene code is comprised of four structural regions, comprising the important N-terminal of function-be actin land (actin-binding domain), annular section (rod domain) that span is very large by the similar body of the spectrin of 24 repetitions form, cysteine enrichment region and C-terminal-be dystrophin associated protein complex land.Research shows that the mutantional hotspot of DMD gene mainly concentrates on annular section, and annular section does not play an important role to the function of dystrophin albumen, thus the excalation of annular section on the function of dystrophin albumen without impact.Above these all for by forcibly regulating and controlling DMD gene mRNA precursor splicing, the DMD gene of sudden change being repaired theoretical basis is provided.
In in the past 15 years, huge directive function has been played in these theoretical development for Du Xing muscular dystrophy splicing corrective gene Therapeutic Method.The process of the most typically applying the splicing of antisense oligonucleotide regulation and control DMD gene mRNA precursor is, antisense oligonucleotide is by the combination with targeting exon and adjacent domain thereof, stop and transcribe the identification of splicing complex to the targeting exon, thereby it is cut away from ripe transcript, complete the process of skipping, produce the correct transcript of reading frame, finally generate the short bioactive dystrophin albumen that has.The antisense oligonucleotide of can inducing exon skipping is comprised of 20-30 oligonucleotide usually, has sequence homology with the mRNA precursor transcript of targeting exon or its near zone.The wherein typical land of targeting antisense oligonucleotide, the normally conserved sequence of target exon or other sites, for example exon enhancer zone.In addition, contiguous intron/exon boundary (for example splicing donor-donor site or acceptor site-acceptor site) or contiguous intron branching-point sequence (branch point) also can be used as the target spot target.
The exon skipping method of antisense oligonucleotide mediation is in the application of Du Xing muscular dystrophy, evidence the earliest comes from the in vitro tests of Human Lymphocytes and mdx mouse muscle fiber cell, these the results shows the feasibility of exon skipping method of antisense oligonucleotide mediation.The exon skipping of at present antisense oligonucleotide mediation has become in Du Xing muscular dystrophy gene treatment field the most successfully, has had most one of Therapeutic Method of application prospect.And existing two kinds of antisense oligonucleotides enter the clinical II/III phase and test, and result of the test is gratifying.
Yet, clinical trial and preclinical study result all show, the system conevying efficiency is low is to comprise that at present the range gene medicine of antisense oligonucleotide needs the difficult problem of solution badly, the height of medicament transport efficiency is one of key factor determined its therapeutic effect, is also the bottleneck of current gene therapy.Therefore develop new transportation system, improving medicament transport efficiency is the task of top priority.
Summary of the invention
The purpose of this invention is to provide the newtype drug targeting transportation adjuvant that a kind of targeting conevying efficiency is high, preparation is simple, side effect is little.
For realizing above-mentioned goal of the invention, technical scheme of the present invention is as follows:
A kind of newtype drug targeting transportation adjuvant, be at least one class in pentose, hexose, sugar alcohol, disaccharide.
Described pentose is selected from least a in xylose, arabinose; Described hexose is selected from least a in glucose, galactose, fructose, mannose; Described disaccharide is selected from least a in sucrose, lactose, maltose, trehalose; Described sugar alcohol is selected from least a in Sorbitol, mannitol, erythritol, maltose alcohol, lactose, xylitol.
Preferably, use following weight fraction combination: glucose, fructose, sucrose=3: 5: 2.
Preferably, use following weight fraction combination: glucose, fructose, sucrose=4: 2: 1.
The present invention also provides the using method of described a kind of newtype drug targeting transportation adjuvant, comprises the steps:
1) prepare sugar juice: proportionally prepare sugar juice, monosaccharide concentration is 50mg/ml, and mixed sugar is proportionally mixed, and total sugar content is 100mg/ml;
2) sugar juice according to concentration described in step 1 transports medicine, dosed administration as requested.
The application of a kind of newtype drug targeting transportation adjuvant of the present invention in the transportation medicine.
The application of a kind of newtype drug targeting transportation adjuvant in the transportation medicine, preferably, for targeting transportation antisense oligonucleotide medicine PMO, PNA, 2 ' ome RNA, peptide-PMO and siRNAs and macromole plasmid.
Further, for the targeting transportation, treat antisense oligonucleotide medicine PMO (phos phorodiamidate mrpholino oligomers), PNA, 2 ' ome RNA, peptide-PMO and siRNAs and the macromole plasmid of Du Xing muscular dystrophy.
PMO is a kind of novel trans MODN, suppresses natural RNA montage process, produces various mRNA, but inhibition of gene expression, if suppressed the expression of proto-oncogene.PMO is combined effectively blocking virus rna transcription of the duplex thing that forms with special virus mRNA, the inhibition virus replication.This compound has again good stability, dissolubility and cell permeability, now for the research of viral infection, cancer, duchenne muscular dystrophy and progeria syndrome medicine.
The full name of 2 ' ome RNA is: 2 '-O-RNA antisense oligonucleotide that methylates, PNA is peptide nucleic acid(PNA), peptide-PMO has connected shuttle back and forth peptide or organize the PMO of targeting peptides of cell, siRNA is a class double stranded rna molecule, above-mentioned substance is common antisense oligonucleotide drug kinds, can regulate and control the expression of mRNA, all can be buied by market.
The invention has the beneficial effects as follows: the targeting transportation is effective, can significantly improve the action effect of medicine in destination organization; Take from natural product-saccharide, without injury, toxic and side effects is little to human body basic.
The accompanying drawing explanation
Fig. 1 is immunohistochemical analysis figure as a result
Fig. 2 is the quantitative analysis figure to the muscle fiber number of the front tibialis cross section dystrophin positive
Fig. 3 is the RT-PCR analysis chart
Fig. 4 is the transportation effect quantitative analysis figure of 2 pairs of four kinds of different antisense oligonucleotide medicines of embodiment
Fig. 5 is the RT-PCR analysis chart of the transportation effect of 2 pairs of four kinds of different antisense oligonucleotide medicines of embodiment
Fig. 6 is the transportation effect quantitative analysis figure that 2,4,5,6,7,11,12 couples of embodiment can regulate and control the siRNA medicine of GAPDH housekeeping gene expression
The specific embodiment
Below principle of the present invention and feature are described, example, only be used to explaining the present invention, is not intended to limit scope of the present invention.
Explanation
Following table is the sugar that embodiment 1-12 selects
Above-mentioned code F1 is normal saline, is medicament transport carrier commonly used, and other pharmaceutical carriers commonly used also have PBS solution etc., and effect is consistent with normal saline.
Above-described embodiment 10 and 11 ratio are glucose: fructose: the weight ratio of sucrose.
The using method of the newtype drug targeting transportation adjuvant of described embodiment is:
Preparation method as the monosaccharide of embodiment 1-9 and 12 is: use the mother solution preparation of the sugar prepared in advance to obtain the monosaccharide solution of concentration as 50mg/ml, according to dosage, medicine is directly added in this monosaccharide solution and gets final product.
For the mixed sugar solution of embodiment 10,11, reach the total sugar concentration of 100mg/ml, according to the ratio of 3: 5: 2, need glucose, fructose, sucrose to be respectively 30mg/ml, 50mg/ml, 20mg/ml.According to the ratio of 4: 2: 1, need glucose, fructose, sucrose to be respectively 57mg/ml, 29mg/ml, 14mg/ml.
The above-mentioned a few class medicines that use, concrete sequence is:
PMO?5′ggccaaacctcggcttacctgaaat3′
PNA?5′ggccaaacctcggcttacct3′
2′OMe?RNA?5′GGCCAAACCUCGGCUUACCU3′
P007 is one section cell peptide that shuttles back and forth, and specifically is disclosed in Human Molecular Genetics, and 2008, Vol.17, in No.24 3909-3918.
Test one
For the effect in the application of drug targeting transportation adjuvant in the transportation medicine, especially the antisense oligonucleotide medicine PMO of transportation treatment Du Xing muscular dystrophy of described embodiment, carried out following experiment:
1 materials and methods:
1) Mdx mice:
Animal model the most commonly used in the research of Du Xing muscular dystrophy gene treatment at present, on its dystrophin gene extron 23, contain a nonsense point mutation, cause dystrophin (dystrophin) protein translation premature termination, thereby can not translate significant dystrophin albumen, therefore this research be take the mdx mice and is test animal, and this mice is purchased from Nanjing of China model animal institute.
2) testing drug:
A kind of antisense oligonucleotide medicine-morpholino (PMO) of take in clinical trial is testing drug, and this medicine is purchased from U.S. Gene Tools company.
3) test method:
Different saccharide compounds is tested in the efficiency of the front tibialis transportation PMO of mice.
2ug PMO is mixed with the certain density sugar juice of embodiment 1-12 respectively, local injection is in the front tibialis of mdx mice, single injection, after 2 weeks, collect the front tibialis tissue of injecting, by SABC, RT-PCR, detect the exon skipping efficiency of PMO mediation and the expression of recovery dystrophin albumen, by the comparison with contrast solution-normal saline, determine the raising effect of different sugar solution to the conevying efficiency of PMO.
Fig. 1 is immunohistochemical analysis figure as a result, and wherein redness is the muscle fiber of the dystrophin positive, blueness is nucleus dyeing (scale bar=200um), c57 is the C57BL6 mice of wild type, can see, after using the medicine of embodiment of the present invention to carry out the PMO transportation, in the front tibialis tissue of mice, the muscle fiber of the dystrophin positive rolls up, show that further PMO is under the transportation of the present embodiment is auxiliary, can significantly recover the expression of dystrophin albumen, with the normal saline of F1, compare, can see intuitively, embodiment 6, 7, 10, 11, 12 dystrophin is positive, and muscle fiber quantity is significantly improved, other embodiment have also reached the effect be equal at least.
Fig. 2 is the quantitative analysis figure of the muscle fiber number of the front tibialis cross section dystrophin positive, the muscle fiber that can see the dystrophin positive of above-described embodiment is counted relative physiologic saline and is increased considerably, and shows that the effect of medicament transport adjuvant of the present invention is better than normal saline greatly.
Fig. 3 is the RT-PCR analysis chart, and in figure, full-length means the PCR do not skipped product; Exon23 is expressed as the PCR product that exon 23 is skipped; Exon22& The 23 PCR products of all skipping for exon 22 and 23, C57 are the C57BL6 mice of wild type, the negative contrast of Ve.Can see in the situation that the transportation adjuvant of embodiment 1-12 transports, exon skipping has clearly occurred, thereby cause the muscle fiber expression of the dystrophin positive to increase.
Test two
In order to prove the remarkable effect of medicament transport adjuvant of the present invention in other antisense oligonucleotide medicines of transportation, using embodiment 2 is that F3 and normal saline have carried out contrast test.
Fig. 5 is the myofibrillar quantitative analysis of the dystrophin positive, four groups of data mean that respectively embodiment 2 and normal saline are to 2 ' ome RNA, PNA, PMO, the transportation effect of P007-PMO, the myofibrillar quantity that directly translates into the dystrophin positive increases, can see four groups of data, use the rear effect of embodiments of the invention 2 all than normal saline, to have significantly and increase.
Fig. 6 is the RT-PCR figure as a result of normal saline and 2 couples of above-mentioned 2 ' ome RNA of embodiment, PNA, PMO, tetra-kinds of medicament transport effects of P007-PMO, can find out that antisense oligonucleotide medicine mediation exon skipping efficiency obviously improves.
Test three
In order to prove the transportation effect of transportation adjuvant of the present invention to the other types medicine for the treatment of other diseases, the applicant selects the GAPDH housekeeping gene to test, and the siRNA medicine of selecting a class can lower its expression is tested.The sugar juice used is embodiment 2,4,5,6,7,11,12, and the basic experiment operation is the same.Fig. 6 is GAPDH housekeeping gene expression quantitative analysis figure, can see, illustrated embodiment all has downward in various degree, with embodiment 2, is the F3 best results especially, and this test has enlarged range of application of the present invention.
The foregoing is only preferred embodiment of the present invention, be not limited to the present invention, within the spirit and principles in the present invention all, any modification of making and be equal to replacement, within all should being included in protection scope of the present invention.
Claims (8)
1. a newtype drug targeting transportation adjuvant, is characterized in that: be at least one class in pentose, hexose, sugar alcohol, disaccharide.
2. a kind of newtype drug targeting transportation adjuvant according to claim 1 is characterized in that: described pentose is selected from least a in xylose, arabinose; Described hexose is selected from least a in glucose, galactose, fructose, mannose; Described disaccharide is selected from least a in sucrose, lactose, maltose, trehalose; Described sugar alcohol is selected from least a in Sorbitol, mannitol, erythritol, maltose alcohol, lactose, xylitol.
3. a kind of newtype drug targeting transportation adjuvant according to claim 2, is characterized in that: preferably, use following weight fraction combination: glucose, fructose, sucrose=3: 5: 2.
4. a kind of newtype drug targeting transportation adjuvant according to claim 2, is characterized in that: preferably, use following weight fraction combination: glucose, fructose, sucrose=4: 2: 1.
5. according to the using method of the described a kind of newtype drug targeting transportation adjuvant of claim 1-4 any one, it is characterized in that: comprise the steps:
1) prepare sugar juice: proportionally prepare sugar juice, monosaccharide concentration is 50mg/ml, and mixed sugar is proportionally mixed, and total sugar content is 100mg/ml;
2) sugar juice according to concentration described in step 1 transports medicine, dosed administration as requested.
6. according to the application of the described a kind of newtype drug targeting transportation adjuvant of claim 1-4 any one in the transportation medicine.
7. according to the application of the described a kind of newtype drug targeting transportation adjuvant of claim 1-4 any one in the transportation medicine, it is characterized in that: preferably, for targeting transportation antisense oligonucleotide medicine PMO, PNA, 2 ' ome RNA, peptide-PMO and siRNAs and macromole plasmid.
8. according to the application of the described a kind of newtype drug targeting transportation adjuvant of claim 1-4 any one in the transportation medicine, it is characterized in that: preferably, for antisense oligonucleotide medicine PMO, PNA, 2 ' ome RNA, peptide-PMO and siRNAs and the macromole plasmid of targeting transportation treatment Du Xing muscular dystrophy.
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| CN201210408148XA CN103405774A (en) | 2012-10-24 | 2012-10-24 | Novel drug targeting delivery adjuvant |
| PCT/CN2013/085627 WO2014063602A1 (en) | 2012-10-24 | 2013-10-22 | New drug targeting delivery adjuvant |
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| CN102459597A (en) * | 2009-05-08 | 2012-05-16 | 欧科库尔纳有限责任公司 | Treatment of dystrophin family related diseases by inhibition of natural antisense transcript to dmd family |
| CN102695797A (en) * | 2009-06-16 | 2012-09-26 | 欧科库尔纳有限责任公司 | Treatment of collagen gene related diseases by inhibition of natural antisense transcript to a collagen gene |
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| EP2125006B1 (en) * | 2007-01-18 | 2013-10-16 | University of Missouri-Columbia | Synthetic mini/micro-dystrophin genes to restore nnos to the sarcolemma |
| WO2009144481A2 (en) * | 2008-05-30 | 2009-12-03 | Isis Innovation Limited | Conjugates for delivery of biologically active compounds |
| CN102000324A (en) * | 2009-09-01 | 2011-04-06 | 天津瑞普生物技术股份有限公司 | Long-efficiency and stable animal interferon solution preparation and preparation method thereof |
| CN102652837A (en) * | 2011-03-01 | 2012-09-05 | 上海交通大学医学院附属第三人民医院 | Medicament for treating colorectal cancer |
| CN102218028B (en) * | 2011-03-24 | 2013-08-14 | 杭州天龙药业有限公司 | Antisense oligonucleotide injection for treating liver cancer and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102459597A (en) * | 2009-05-08 | 2012-05-16 | 欧科库尔纳有限责任公司 | Treatment of dystrophin family related diseases by inhibition of natural antisense transcript to dmd family |
| CN102695797A (en) * | 2009-06-16 | 2012-09-26 | 欧科库尔纳有限责任公司 | Treatment of collagen gene related diseases by inhibition of natural antisense transcript to a collagen gene |
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