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EP-4736880-A1 - NUCLEIC ACID DELIVERY COMPOSITION AND NUCLEIC-ACID-CONTAINING COMPOSITION

EP4736880A1EP 4736880 A1EP4736880 A1EP 4736880A1EP-4736880-A1

Abstract

Provided is a nucleic acid delivery composition which can deliver nucleic acid therapeutics to central nervous system tissues by nasal administration with high efficiency and can form composite particles with good physical stability and uniformity. The nucleic acid delivery composition of the present invention is a nucleic acid delivery composition used to deliver a nucleic acid to central nervous system tissues or the trigeminal nerve, containing a block copolymer (I) having a polyethylene glycol segment (a) and a polycaprolactone segment (b) and a peptide (II) including 8 to 20 amino acid residues modified with a fatty acid, wherein in the block copolymer (1), the average molecular weight Ma of the polyethylene glycol segment (a) is 1,500 to 2,500 or 3,500 to 6,500, and the average molecular weight Mb of the polycaprolactone segment (b) is 1.5 to 3 times the average molecular weight Ma of the polyethylene glycol segment (a), and the nucleic acid delivery composition is delivered to central nervous system tissues or the trigeminal nerve by nasal administration.

Inventors

  • KANAZAWA TAKANORI
  • IIOKA Shingo
  • KONDO HIROMU

Assignees

  • Tokushima University

Dates

Publication Date
20260506
Application Date
20240524

Claims (11)

  1. A nucleic acid delivery composition used to deliver a nucleic acid to central nervous system tissues or trigeminal nerve, comprising a block copolymer (I) having a polyethylene glycol segment (a) and a polycaprolactone segment (b), and a peptide (II) comprising 8 to 20 amino acid residues modified with a fatty acid, wherein in the block copolymer (I) an average molecular weight Ma of the polyethylene glycol segment (a) is 1,500 to 2,500 or 3,500 to 6,500, an average molecular weight Mb of the polycaprolactone segment (b) is 1.5 to 3 times the average molecular weight Ma of the polyethylene glycol segment (a), and the nucleic acid delivery composition is delivered to the central nervous system tissues or trigeminal nerve by nasal administration.
  2. The nucleic acid delivery composition according to claim 1, wherein in the block copolymer (I), the average molecular weight Mb of the polycaprolactone segment (b) is 3,500 to 6,500 or 8,000 to 12,000.
  3. The nucleic acid delivery composition according to claim 1, wherein a mixing ratio of the block copolymer (I) and the peptide (II) is (I) : (II) = 0.25 : 1 to 2 : 1 by mole ratio.
  4. The nucleic acid delivery composition according to claim 1, wherein the block copolymer (I) is methoxypolyethylene glycol-poly(ε-caprolactone).
  5. The nucleic acid delivery composition according to claim 1, wherein the peptide (II) is a peptide comprising cysteine residues, histidine residues and arginine residues, and the fatty acid modifying the peptide is stearic acid.
  6. The nucleic acid delivery composition according to claim 1, wherein the block copolymer (I) and the peptide (II) form nanoparticles.
  7. The nucleic acid delivery composition according to claim 6, wherein the nanoparticles have an average particle diameter of 50 nm or less, a polydispersity index (PDI) of 0.3 or less and a zeta potential of 1 to 20 mV.
  8. A nucleic acid-containing composition, further comprising a nucleic acid in the nucleic acid delivery composition according to any one of claims 1 to 7.
  9. The nucleic acid-containing composition according to claim 8, wherein a ratio (N/P ratio) of a total number of moles (N) of cationic groups derived from the peptide (II) and a total number of moles (P) of phosphate groups derived from the nucleic acid is 3 to 30.
  10. The nucleic acid-containing composition according to claim 8, wherein the nucleic acid is an antisense oligonucleotide, siRNA or mRNA for treating a disease in central nervous system tissues.
  11. A medicine comprising the nucleic acid-containing composition according to claim 8 as an active ingredient.

Description

TECHNICAL FIELD The present invention relates to a nucleic acid delivery composition and a nucleic acid-containing composition used to deliver a nucleic acid to a target tissue, and particularly to a nucleic acid delivery composition and a nucleic acid-containing composition which can deliver a nucleic acid to central nervous system tissues such as the brain and spinal cord or the trigeminal nerve by nasal administration. BACKGROUND ART For central nervous system (CNS) diseases such as neurodegenerative diseases, brain tumors, cerebrovascular disorders and brain infectious diseases for which effective therapeutic agents have not existed until now, nucleic acid therapeutics which can knock down CNS disease-related molecules at the mRNA level have been studied. Currently Nusinersen (a medicine for treating spinal muscular atrophy intended for patients with SMN gene mutation) and Tofersen (a medicine for treating amyotrophic lateral sclerosis intended for patients with SOD1 gene mutation), for example, have been developed as nucleic acid therapeutics for CNS diseases. These, however, all are applied to patients by intrathecal administration and have high invasiveness and high burden to patients. The nose-to-brain route by nasal administration, meanwhile, has attracted attention as a novel drug transport route to the central nervous system. In this route, a drug directly reaches the central nervous system through neural circuits (olfactory nerve and trigeminal nerve) from the nasal mucosa. Therefore, both an efficient drug transport to the central nervous system not passing through the blood-brain barrier and a reduction in adverse effects on peripheral organs, non-target tissues, can be expected. The present inventors have studied a drug delivery technique via the nose-to-brain route and, as one of the study results, found and reported that a compound obtained by binding a predetermined cell-penetrating peptide to a block copolymer in which a polyethylene glycol segment and a hydrophobic polyester segment are connected, on another terminal side of the hydrophobic polyester segment (the terminal side which is not connected to the polyethylene glycol segment) formed nanoparticles having a micelle structure and functioned as a drug delivery composition which delivers a drug to the spinal cord by nasal administration (Patent Literature 1). CITATION LIST PATENT LITERATURE Patent Literature 1: Japanese Patent No. 7211603 SUMMARY OF INVENTION TECHNICAL PROBLEM The nanoparticles formed by the drug delivery composition reported in Patent Literature 1, however, had problems in that the particle size distribution was wide and uniformity was poor and moreover the average particle diameter and zeta potential, for example, were easily changed over days and physical stability was poor. The present invention therefore has been made in view of the above-described points and an object thereof is to provide a nucleic acid delivery composition which can deliver nucleic acid therapeutics to central nervous system tissues with high efficiency by nasal administration and can form composite particles having good physical stability and uniformity. The compound used in the drug delivery composition reported in Patent Literature 1 is obtained by binding the block copolymer and the predetermined cell-penetrating peptide and thus steps of, for example, the synthesis reaction thereof and purification have spent time and effort (costs). Therefore, another object of the present invention is to provide a composition which does not require a complex synthesis reaction for the bond between the block copolymer and the peptide and is obtained from components which can be easily acquired. SOLUTION TO PROBLEM The present inventors aimed at highly efficient delivery of nucleic acid therapeutics to central nervous system tissues by nasal administration and diligently studied combinations of block copolymers having various structures and a predetermined functional peptide. Consequently, the present inventors found a nucleic acid delivery composition which can highly efficiently deliver nucleic acid therapeutics to central nervous system tissues and forms composite particles having good physical stability and uniformity. Based on the knowledge, the present invention was completed. In order to solve the above problems, the nucleic acid delivery composition of the present invention is a nucleic acid delivery composition used to deliver a nucleic acid to central nervous system tissues or the trigeminal nerve, the nucleic acid delivery composition containing a block copolymer (I) having a polyethylene glycol segment (a) and a polycaprolactone segment (b) and a peptide (II) including 8 to 20 amino acid residues modified with a fatty acid, wherein in the block copolymer (I), the average molecular weight Ma of the polyethylene glycol segment (a) is 1,500 to 2,500 or 3,500 to 6,500 and the average molecular weight Mb of the polycaprolactone segment (b) is 1.5