JP2017082002A - Nucleic acid transfer carrier - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a clinically applicable nucleic acid transfer carrier which is less toxic and capable of being administered topically or systemically and which increases the reaching efficiency and the introduction efficiency of nucleic acid pharmaceuticals to the affected site to be treated.SOLUTION: The present invention provides nucleic acid transfer carrier containing a peptide surfactant.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a nucleic acid transfer carrier containing a peptide surfactant.

  RNA interference (RNAi) is a phenomenon in which the expression of a specific gene is suppressed by a short double-stranded RNA, and is expected to be applied to the treatment of diseases. In the current technology, a transport carrier when using small interfering RNA (siRNA) or micro RNA (miRNA) as a nucleic acid drug is mainly a cationic phospholipid, but its toxicity has been pointed out. In addition, research using atelocollagen as a transport carrier has been carried out, but further improvement is necessary to improve its therapeutic effect.

  Considering the clinical application of nucleic acid drugs including siRNA, it is desirable that the carrier for transferring the nucleic acid drug to the affected area is as low in toxicity as possible, and at the same time, the arrival efficiency to the affected area and the suppression efficiency of the target gene are high. Development of a carrier that can be administered systemically is awaited.

  The peptide surfactant of the present invention is known to have an action of stabilizing membrane proteins such as G protein-coupled receptor bovine rhodopsin and a property of self-assembly (Non-patent Documents 1 and 2). However, its use as a nucleic acid transfer carrier has not been known so far.

X Zhao et al. , PNAS, Vol. 103, no. 47, 17707-17712 A Nagai et al. , J .; Nanosci. Nanotechnol. Vol. 7, no. 7, 1-7

  The problem to be solved by the present invention is to provide a nucleic acid transfer carrier that is less toxic, can reach the affected area, and has a high efficiency of suppressing the target gene, which can be applied clinically.

  As a result of intensive studies to solve the above problems, the present inventors have surprisingly found that a peptide surfactant is useful as a nucleic acid transfer carrier and completed the present invention.

Therefore, the present invention is as follows.
[1] A nucleic acid transfer carrier containing a peptide surfactant.
[2] The nucleic acid transfer carrier according to [1], wherein the peptide surfactant comprises a head composed of 4 to 10 hydrophilic amino acids and a tail composed of 1 or 2 hydrophobic amino acids.
[3] The nucleic acid transfer carrier according to [1], wherein the nucleic acid transfer carrier is AAAAAAD or AAAAAAK.
[4] A medicinal product for local administration or systemic administration comprising the nucleic acid transfer carrier according to any one of [1] to [3] above and a nucleic acid.

  The nucleic acid transfer carrier of the present invention is less toxic, can be administered locally and systemically, and has the effect of increasing the reach efficiency and introduction efficiency of the nucleic acid drug to the affected area.

It is confirmation of the gene expression suppression effect in the local administration of siRNA by a peptide surfactant. “Si-” means an experimental group in which no siRNA was added to the peptide surfactant, and siRNA was added to the peptide surfactant in the other groups. It is confirmation of the gene expression inhibitory effect in the systemic administration of siRNA by a peptide surfactant. “Si-” means an experimental group in which no siRNA was added to the peptide surfactant, and siRNA was added to the peptide surfactant in the other groups. It is confirmation of the tumor cell growth inhibitory effect by local administration of siRNA by a peptide surfactant. It is confirmation of the inhibitory effect of the tumor cell growth gene in local administration of siRNA by a peptide surfactant. It is confirmation of the tumor cell growth inhibitory effect in the systemic administration of siRNA by a peptide surfactant. Serum GOT concentration. Serum GPT concentration. Serum interferon alpha concentration. Serum interferon gamma concentration. Serum MCP-1 concentration. Serum interleukin 12 concentration. Serum interleukin 6 concentration. Serum chemokine concentration.

  In the present invention, a peptide surfactant includes 6 to 10 amino acid residues and has a length of about 2 to 3 nm, and is a conventional surfactant such as n-dodecyl-β. It exhibits the same characteristics as -D-maltoside (DM) and octyl-D-glucoside (OG).

  The peptide surfactant of the present invention preferably comprises a head composed of 4 to 10 hydrophilic amino acids and a tail composed of 1 or 2 hydrophobic amino acids.

  More specifically, GGGGDD (G4D2), GGGGGGD (G6D), GGGGGGDD (G6D2), GGGGGGGGD (G8D), GGGGGGGGGDD (G8D2), GGGGGGGGGD (G10D), G4 , GGGGGGGGK (G8K), GGGGGGGGKK (G8K2), GGGGGGGGGGGK (G10K), GGGGGGGGGGKK (G10K2), GGGGGGGGGGDD (G10D2), AAAADD (A4D2), AAAAAAD (A6D), AAAAAADD (A6D2), AAAAAAAAD (A8D), AAAAAAAADD (A8D2) , AAAAAAAAAAD (A10D), AAAAAAAAAAD (A10D2), AAAAAKK (A4K2), AAAAAAAK (A6K), AAAAAAAKK (A6K2), AAAAAAAAK (A8K), AAAAAAAKK (A10AV), AAAAAAV (V6D2), VVVVVVVVD (V8D), VVVVVVVVDD (V8D2), VVVVVVVVVVD (V10D), VVVVVVVVVVDD (V10D2), VVVVKK (V4K2), VVVVVVK (V6K), VVVVVVKK (V6K2), VVVVVVVVK (V8K), VVVVVVVVKK (V8K2), VVVVVVVVVVK (V10K), VVVVVVVVVVK (V10K2), LLLLDDD (L4D2), LLLLLLDLD (L6D), LLLLLLLDD (L6D2), LLLLLLLLD (L8D), LLLLLLLKLD (L8D2), LLLLLLLLLKD (L10L2L, LLL) LLLLLLLLLK (L8K), LLLLLLLLLKKK (L8K2), LLLLLLLLLKLK (L10K), and LLLLLLLLLLKK (L10K2) are preferable, among which AAAAAAA (A6A) or AAAAAAK (A6AA is preferable).

  The peptide surfactant is produced by a solid phase synthesis method or a liquid layer synthesis method. Since the peptide can be artificially synthesized, it does not contain biological substances and there is no risk of infection.

  In the present invention, the nucleic acid transfer carrier refers to a composition that can be used to transfer a polynucleotide or gene such as siRNA to a tissue intended by a living body and introduce a gene, and to increase its arrival efficiency and introduction efficiency. .

Examination of RNAi effect in mouse local administration model In mice with tumor cells that express luciferase gene, a solution containing siRNA and peptide surfactant mixed with luciferase gene is directly injected into tumor, and siRNA introduction and gene suppression effect is luciferase luminescence As a result, the gene suppression effect of the siRNA / peptide surfactant mixed solution was confirmed.

<Material>
・ Peptide surfactant sequence: Ac-AAAAAAK-NH2, manufactured by Celtek ・ Peptide surfactant concentration 2 concentration: 50 μg / mL, 500 μg / mL
・ Luciferase gene suppression siRNA
Luciferase GL3 siRNA (B-Bridge International, Inc., Luciferin Luciferin 1 g (Wako)) was dissolved in 66.7 mL of Dulbecco's PBS (without Mg ²⁺ , Ca ²⁺ ) and sterilized through a 0.2 μm syringe filter (Minisart). The solution was directly dispensed into a light-shielding tube through a syringe filter and stored at −80 ° C. (−20 ° C.).
-Luciferase gene expression tumor cells PC-3M-luc-C6 (Xenogen, Alameda)

<Method>
- mouse tumor model creation PC-3M-luc-C6 cells 10% FBS (Equitech-Bio, Kerrville) 37 ℃ at containing Eagle's MEM medium (Invitrogen), and incubated under 5% CO _2. PC-3M-luc-C6 cells were collected by trypsin treatment, suspended in Dulbecco's PBS (without Mg ²⁺ , Ca ²⁺ ), and 3 × 10 ⁶ subcutaneously in 9-week-old male nude mice (CLEA Japan, Osaka). Cells / 200 μl were transplanted with a 26G injection needle to prepare tumor mice.
-Preparation of siRNA / peptide surfactant: 50 μg of Luciferase GL3 siRNA (dissolved in 100 μL of PBS (−)) and an equal amount of peptide surfactant (prepared so that the final dose is 200 μL per mouse), and 20 at room temperature Rotate and mix at low speed for minutes.
In the administration test group, 200 μl of siRNA / peptide surfactant mixed solution was administered per tumor site. On the other hand, in the control group, only 200 μl of peptide surfactant (50 μg / mL and 500 μg / mL) was administered.
In vivo imaging The body weight of the animals was measured before luciferin administration, and a luciferin solution (15 mg / mL) was intraperitoneally administered at 150 mg / kg with a 26G injection needle (Terumo). Ten minutes after the administration of luciferin, imaging was performed with IVIS Imaging System (Xenogen). Imaging data was analyzed with LIVINGIMAGE 2.51 software (Xenogen). Luciferase luminescence imaging was performed from day 0 to day 2 with day 0 immediately before siRNA administration, and the change in the amount of luminescence was regarded as the siRNA suppression effect.

<Result>
The results are shown in FIG. In the control group (peptide surfactant only), the amount of luciferase luminescence increased after administration, whereas the amount of luminescence decreased in the test group. From this, it was considered that mixing siRNA with a peptide surfactant promotes siRNA introduction into tumor cells and suppresses gene expression.

Examination of RNAi effect in mouse systemic administration model To mice with tumors that express luciferase gene, a mixture of luciferase gene-suppressing siRNA and peptide surfactant is administered from the tail vein, and siRNA introduction and gene-suppressing effect are controlled by luciferase luminescence. Analysis by imaging confirmed the gene suppression effect of the siRNA / peptide surfactant mixture.

<Material>
・ Peptide surfactant sequence: Ac-AAAAAAK-NH2, manufactured by Celtek ・ Peptide surfactant concentration 2 concentration: 50.0, 500.0 μg / mL
・ Luciferase gene suppression siRNA
Luciferase GL3 siRNA (B-Bridge International, Inc.)
-Luciferin 1 g (Wako) of luciferin was dissolved in 66.7 mL of Dulbecco's PBS (Mg ²⁺ , Ca ²⁺ free) and sterilized through a 0.2 μm syringe filter (Minisart). The solution was directly dispensed into a light-shielding tube through a syringe filter and stored at −80 ° C. (−20 ° C.).
-Luciferase gene expression tumor cells PC-3M-luc-C6 (Xenogen, Alameda)

<Method>
Creating a mouse tumor model PC-3M-luc-C6 cells 10% FBS (Equitech-Bio, Kerrville) 37 ℃ at containing Eagle 's MEM medium (Invitrogen), 5% CO ₂ culture under. PC-3M-luc-C6 cells were collected by trypsinization, suspended in Dulbecco's PBS (without Mg ²⁺ , Ca ²⁺ ), and 1.25 × subcutaneously in 9 week old male nude mice (CLEA Japan, Osaka). Implanted with a 26G needle at 10 ⁶ cells / 200 μl.
・ Preparation of siRNA / peptide surfactant 50 μg of Luciferase GL3 siRNA (dissolved in 100 μL of PBS (−)) and peptide surfactant were mixed in equal amounts (prepared so that the final dose was 200 μL per mouse), and at room temperature Spin-mixed at low speed for 20 minutes.
In the administration test group, 200 μl of siRNA / peptide surfactant mixed solution was administered from the tail vein of the mouse with a 27G injection needle (manufactured by Terumo). In the control group, 200 μl of peptide surfactant (500 μ / mL) alone was administered.
In vivo imaging The body weight of the animals was measured before luciferin administration, and a luciferin solution (15 mg / mL) was intraperitoneally administered at 150 mg / kg with a 26G injection needle (Terumo). Ten minutes after the administration of luciferin, imaging was performed with IVIS Imaging System (Xenogen). Imaging data was analyzed with LIVINGIMAGE 2.51 software (Xenogen). Luciferase luminescence imaging was performed from day 0 to day 2 with day 0 immediately before siRNA administration, and the change in the amount of luminescence was regarded as the siRNA suppression effect.

<Result>
The results are shown in FIG. In the control group (surfactant only), the amount of luciferase luminescence increased on the second day after administration, but in the test group, the issued amount decreased. From this, it was considered that when siRNA was mixed with a peptide surfactant and administered systemically, introduction of siRNA into tumor cells was promoted by the peptide surfactant and gene expression was suppressed.

Examination of RNAi effect in a mouse model for local administration In mice with tumor cells expressing luciferase gene, a solution containing siRNA and peptide surfactant mixed with cell growth inhibitory effect is directly injected into the tumor, and the cell growth inhibitory effect is shown in tumor size When analyzed by measurement, the cell growth inhibitory effect of the siRNA / peptide surfactant mixed solution was confirmed.

<Material>
・ Peptide surfactant sequence: Ac-AAAAAAK-NH ₂ , manufactured by Celtek ・ Peptide surfactant concentration 500 μg / mL
・ Tumor cell inhibitory siRNA
EZH2 siRNA (manufactured by Sigma)
・ Negative control siRNA
AllStars Negative Control siRNA (QIAGEN)
-Luciferin 1 g (Wako) of luciferin was dissolved in 66.7 mL of Dulbecco's PBS (Mg2 +, Ca2 + free) and sterilized through a 0.2 μm syringe filter (Minisart). Dispense directly into light-shielding tube through syringe filter and store at -80 ° C (-20 ° C).
-Luciferase gene expression tumor cells PC-3M-luc-C6 (Xenogen, Alameda)

<Method>
-Preparation of tumor model mice PC-3M-luc-C6 cells are cultured in Eagle's MEM medium (Invitrogen) containing 10% FBS (Equitech-Bio, Kerrville) at 37 ° C under 5% CO2. PC-3M-luc-C6 cells were collected by trypsin treatment, suspended in Dulbecco's PBS (without Mg2 +, Ca2 +), and subcutaneously 2 × 10 ⁶ cells / 9 weeks old male nude mice (CLEA Japan, Osaka) / 200 μl is transplanted with a 26G needle to produce tumor mice.
-Preparation of siRNA / Peptide Surfactant 25 µg of siRNA and peptide surfactant were mixed in equal amounts (final amount was 200 µL per mouse), and mixed by rotation at low speed for 20 minutes at room temperature.
In the administration test group, 200 μl of EZH2 siRNA / peptide surfactant mixed solution was administered per tumor site. On the other hand, the control group was administered with 200 μl of AllStars Negative Control siRNA / peptide surfactant mixed solution per tumor. Administration was performed three times, day 0, day 4, and day 8.
・ Measurement of tumor size The short diameter, long diameter, and height measurement by digital calipers is performed on day 0, day 4, and day 8 immediately before siRNA administration, and the change in tumor size (product of three sides) is taken as the tumor cell proliferation inhibitory effect .

<Result>
The results are shown in FIG. In the control group, the tumor size was increased by day 4, day 8 after administration, but the tumor size was decreased in the test group. From this, it was considered that siRNA introduction into tumor cells was promoted by mixing siRNA with a peptide surfactant, and growth of tumor cells was suppressed.

Examination of RNAi effect in a mouse local administration model Mice with tumor cells expressing luciferase gene are directly injected into tumor with a mixture of siRNA having a tumor growth inhibitory effect and a peptide surfactant, and the amount of target gene mRNA is quantified. Analysis by PCR confirmed the inhibitory effect of the target gene by the siRNA / peptide surfactant mixture.

<Material>
・ Peptide surfactant sequence: Ac-AAAAAAK-NH ₂ , manufactured by Celtek ・ Peptide surfactant concentration 500 μg / mL
・ Tumor growth inhibitory siRNA
EZH2 siRNA (manufactured by Sigma)
・ Negative control siRNA
AllStars Negative Control siRNA (QIAGEN)
-Luciferase gene expression tumor cells PC-3M-luc-C6 (Xenogen, Alameda)

<Method>
-Preparation of tumor model mouse PC-3M-luc-C6 cells are cultured in Eagie's MEM medium (Invitrogen) containing 10% FBS (Equitech-Bio, Kerrville) at 37 ° C under 5% CO2. PC-3M-luc-C6 cells were collected by trypsin treatment, suspended in Dulbecco's PBS (without Mg2 +, Ca2 +), and subcutaneously 2 × 10 ⁶ cells / 9 weeks old male nude mice (CLEA Japan, Osaka) / 200 μl is transplanted with a 26G needle to produce tumor mice.
-Preparation of siRNA / Peptide Surfactant 25 µg of siRNA and peptide surfactant were mixed in equal amounts (final amount was 200 µL per mouse), and mixed by rotation at low speed for 20 minutes at room temperature.
In the administration test group, 200 μl of EZH2 siRNA / peptide surfactant mixed solution was administered per tumor site. On the other hand, the control group was administered with 200 μl of AllStars Negative Control siRNA / peptide surfactant mixed solution per tumor. Administration was continuous for 3 days.
-Tissue fixation / storage test The tumors in the test group and the control group were excised on day 6, stored in liquid nitrogen, and stored frozen at -80 ° C until use.
-RNA extraction The tumor was homogenized, and RNA was extracted using ISOGEN (Nippon Gene).
Synthesis of cDNA siRNA was reverse-transcribed into cDNA using High-Capacity cDNA Reverse Transcription Kits with RNAse Inhibitor (Applied Biosystems).
Real-time PCR
Platinum Quantitative PCR SuperMix-UDG (manufactured by Invirotogen) and Taqman Probe (manufactured by Applied Biosystems) were used to target EZH2 and GAPDH was used as an internal standard to perform quantitative analysis using an Applied Biosystems 7700 real-time PCR system.

<Result>
The results are shown in FIG. When the EZH2 mRNA expression level in the control group was 1, the EZH2 mRNA expression level in the test group was 0.53. From this, the target gene suppression effect in a tumor cell was confirmed by mixing siRNA with a peptide surfactant.

Examination of RNAi effect in a mouse systemic administration model A mouse mixed with a tumor expressing the luciferase gene via the tail vein is administered with a solution containing siRNA having a tumor growth inhibitory effect and a peptide surfactant from the tail vein to treat systemic cancer. When the metastasis inhibitory effect was analyzed by luciferase luminescence imaging, the systemic cancer metastasis inhibitory effect of the siRNA / peptide surfactant mixed solution was confirmed.

<Material>
・ Peptide surfactant sequence: Ac-AAAAAAK-NH ₂ , manufactured by Celtek ・ Peptide surfactant concentration 500.0 μg / mL
・ Tumor growth inhibitory siRNA
EZH2 siRNA (manufactured by Sigma)
KIF11 siRNA (Ambion)
・ Negative control siRNA
AllStars Negative Control siRNA (QIAGEN)
Luciferin 1 g (Wako) of luciferin was dissolved in 66.7 mL of Dulbecco's PBS (Mg2 +, Ca2 + free) and sterilized through a 0.2 um syringe filter (Minisart). Dispense directly into light-shielding tube through syringe filter and store at -80 ° C (-20 ° C).
-Luciferase gene expression tumor cells PC-3M-luc-C6 (Xenogen, Alameda)

<Method>
-Preparation of tumor model mice PC-3M-luc-C6 cells were cultured in Eagle's MEM medium (Invitrogen) containing 10% FBS (Equitech-Bio, Kerrville) at 37 ° C under 5% CO2. PC-3M-luc-C6 cells were collected by trypsin treatment, suspended in Dulbecco's PBS (without Mg2 +, Ca2 +), and 2 × 10 ⁶ cells in the tail vein of 9-week-old male skid mice (CLEA Japan, Osaka). / Implanted with a 26 G needle at 200 μl.
-Preparation of siRNA / Peptide Surfactant 50 μg of each siRNA and peptide surfactant were mixed in equal amounts (the final amount was 200 μL per mouse), and mixed at a low speed for 20 minutes at room temperature.
In the administration test group, 200 μl of EZH2 siRNA or KIF11 siRNA / peptide surfactant mixed solution was administered from a mouse tail vein with a 27G injection needle (manufactured by Terumo). In the control group, 200 μl of AllStars Negative Control siRNA / peptide surfactant mixed solution was administered from the tail vein with a 27G injection needle (manufactured by Terumo).
In vivo imaging The body weight of the animals was measured before luciferin administration, and a luciferin solution (15 mg / mL) was intraperitoneally administered at 150 mg / kg with a 26G injection needle (Terumo). Ten minutes after the administration of luciferin, imaging was performed with an IVISImaging System (Xenogen). Imaging data was analyzed with LIVINGIMAGE 2.51 software (Xenogen). In luciferase luminescence imaging, day 0 immediately before siRNA administration was set to day 0, and day 0, day 9, day 12, and day 15 were performed.

<Result>
The results are shown in FIG. In the control group (surfactant only), an increase in luciferase luminescence was confirmed from day 6 after administration, but no increase in luciferase luminescence was confirmed in the test group. From this, it was considered that when siRNA was mixed with a peptide surfactant and administered systemically, introduction of siRNA into tumor cells was promoted by the peptide surfactant and systemic cancer metastasis was suppressed.

Examination of the effect of surfactant peptide on liver function The siRNA / surfactant peptide mixture was administered to normal mice via the tail vein, and serum GOT and GPT concentrations were measured to confirm that there was no liver toxicity.

<Material>
・ Peptide surfactant sequence: Ac-AAAAAAK-NH ₂ , manufactured by Celtek ・ Peptide surfactant concentration 500.0 μg / mL
・ SiRNA
AllStars Negative Control siRNA (QIAGEN)
Poly (I: C) (manufactured by Sigma)

<Method>
-Preparation of siRNA / Peptide Surfactant 50 μg of each siRNA and peptide surfactant were mixed in equal amounts (final amount was 200 μL per mouse), and rotated and mixed at low speed for 20 minutes at room temperature.
Sample preparation 200 μl of 9-week-old male ICR mice (CLEA Japan, Osaka) was administered to the tail vein with a siRNA / peptide surfactant mixed 27G injection needle (manufactured by Terumo), and blood was collected from the abdominal vena cava 6 hours later . Serum was separated by centrifugation at 1000 xg for 15 minutes.
-Measurement GOT and GPT were measured by Fuji Dry Chem (Fuji Film Co., Ltd.).

<Result>
The results are shown in FIGS. In the test group, serum GOT and GPT values were normal. From this, it was clarified that even if a mixed solution of siRNA and peptide surfactant was systemically administered, the liver function did not change and there was no liver toxicity.

Examination of immunoresponsiveness by surfactant peptide SiRNA / surfactant peptide mixed solution is administered to normal mice via tail vein, and serum interferon alpha, interferon gamma, MCP-1, interleukin 12, interleukin 6 is obtained by ELISA. The chemokine concentration was measured, and it was confirmed that there was no immune response.

<Material>
・ Peptide surfactant sequence: Ac-AAAAAAK-NH ₂ , manufactured by Celtek ・ Peptide surfactant concentration 500.0 μg / mL
・ SiRNA
AllStars Negative Control siRNA (QIAGEN)

<Method>
-Preparation of siRNA / Peptide Surfactant 50 μg of each siRNA and peptide surfactant were mixed in equal amounts (final amount was 200 μL per mouse), and rotated and mixed at low speed for 20 minutes at room temperature.
Sample preparation 200 μl of 9-week-old male ICR mice (CLEA Japan, Osaka) was administered to the tail vein with a siRNA / peptide surfactant mixed 27G injection needle (manufactured by Terumo), and blood was collected from the abdominal vena cava 6 hours later . Serum was separated by centrifugation at 1000 xg for 15 minutes.
Measurements Interferon alpha, interferon gamma, MCP-1, interleukin 12, interleukin 6, and chemokine concentrations were measured by Procarta Cytokine Assay (Panomics).

<Result>
The results are shown in FIGS. 8, 9, 10, 11, 12, and 13. A comparison was made between the control group (non-administration group) and the test group, and no difference was observed in serum interferon alpha, interferon gamma, MCP-1, interleukin 12, interleukin 6, and chemokine concentrations. From this, it was clarified that an immune response reaction was not induced even when a mixed solution of siRNA and a peptide surfactant was systemically administered.

<General consideration>
In combination with the results of Example 1 and Example 2, it was considered that the peptide surfactant is useful for suppressing gene expression by siRNA both in local administration and systemic administration.
In combination with the results of Example 3, Example 4, and Example 5, it was considered that the peptide surfactant is useful for suppressing tumor cell growth by siRNA both in local administration and systemic administration.
Combining the results of Example 6 and Example 7, the peptide surfactant was considered to be a safe nucleic acid transfer carrier for the living body because it has no hepatotoxicity and does not elicit an immune reaction.

Claims (4)

  A nucleic acid transfer carrier comprising a peptide surfactant.   The nucleic acid transfer carrier according to claim 1, wherein the peptide surfactant comprises a head composed of 4 to 10 hydrophilic amino acids and a tail composed of 1 or 2 hydrophobic amino acids.   The nucleic acid transfer carrier according to claim 1, wherein the nucleic acid transfer carrier is AAAAAAAD or AAAAAAK.   A medicinal product for local administration or systemic administration comprising the nucleic acid transfer carrier according to any one of claims 1 to 3 and a nucleic acid.