CN-121987802-A - Amino acid group aggregate and preparation method and application thereof

Abstract

The invention discloses an amino acid group aggregate and a preparation method and application thereof. Adding at least two amino acids modified by hydrophobic groups into water, adjusting pH value to dissolve, and adjusting pH value to a specific value to obtain amino acid group aggregate. The obtained amino acid-based aggregate can replace the existing peptide aggregate, so that the cost of delivering drugs is reduced, and in addition, a series of amino acid-based aggregates with pH windows are obtained by changing the modification groups and the modification positions so as to meet the pH response requirements of various application scenes.

Inventors

• LI JUNBAI
• Yu Fanchen

Assignees

• 中国科学院化学研究所

Dates

Publication Date

20260508

Application Date

20260113

Claims (9)

1. 1. A method for preparing an amino acid-based aggregate comprises the steps of adding an amino acid modified with a hydrophobic group to water, adjusting pH to dissolve the amino acid, and adjusting pH to a specific value; Wherein the hydrophobic group modified amino acid contains at least two hydrophobic groups; The hydrophobic group is selected from C 1 -C 6 straight-chain or branched-chain alkyl, -CH 2 -Ar (Ar represents an aromatic group), C 1 -C 6 straight-chain or branched-chain alkoxy, -C (=O) -O-R (R is an aromatic group or C 1 -C 6 straight-chain or branched-chain alkyl).
2. 2. The method of claim 1, wherein the aryl group is phenyl; The aryl is a substituted or unsubstituted aryl, and the substituent in the substituted aryl is at least one of hydroxyl, amino, C 1 -C 6 straight-chain or branched-chain alkyl and C 1 -C 6 straight-chain or branched-chain alkoxy.
3. 3. The method of claim 1, wherein the two hydrophobic groups are each independently selected from at least one of Bn, cbz, boc, tBu, iPr, OMe; the amino acid is glycine.
4. 4. The method of claim 1, wherein the hydrophobic group modified amino acid is at least one of the following compounds: Wherein, the 、 、 、 。
5. 5. The method of claim 1, wherein the hydrophobic group modifies the amino group of the amino acid such that the pH window of the formed aggregate is acidic; the hydrophobic group is modified at the carboxyl end of the amino acid, so that the pH window of the formed aggregate is alkaline; Modification of both amino and carboxyl groups with hydrophobic groups results in the formation of aggregates both in acidic and basic conditions, i.e., the pH window for the aggregates is 1-14.
6. 6. An amino acid-based aggregate produced by the method of any one of claims 1 to 5.
7. 7. The use of the amino acid-based aggregate of claim 6 for the preparation of an oral drug delivery system, said drug being a hydrophobic drug.
8. 8. A curcumin @ amino acid based coacervate drug delivery system, wherein said amino acid based coacervate is a Boc-G (-Bn) coacervate.
9. 9. Use of a curcumin @ amino acid based coacervate drug delivery system according to claim 8 for the preparation of a medicament for the treatment of acute colitis.

Description

Amino acid group aggregate and preparation method and application thereof Technical Field The invention belongs to the field of medicines, and particularly relates to an amino acid-based aggregate, a preparation method and application thereof, and more particularly relates to a method for preparing an amino acid-based aggregate by adopting amino acid modified by a hydrophobic group and application of the prepared amino acid-based aggregate in preparation of an oral drug delivery system. Background Peptides are polymers composed of amino acids. The formation of aggregates of peptides by liquid-liquid phase separation (LLPS) is a ubiquitous process in organisms. The existing decal-spacer (stickers-and-spaces) model considers that the liquid-liquid phase separation of peptides results from the proper balance of attractive and unattractive forces between their different amino acid residues, with oppositely charged, aromatic or hydrophobic residues being attractive, called "decals", and hydrophilic residues being amino acids ensuring that the coacervate retains bound water to remain liquid, called "spacers". The peptide aggregate has the advantages of high drug loading rate, high biocompatibility, simple formula, no organic solvent, non-endocytic way into cells, pH regulation and the like, so the peptide aggregate becomes an emerging drug delivery carrier. Most of the peptide aggregates are now formed from polypeptides because the long sequences of polypeptides increase the multivalent nature of the interactions compared to short peptides, which are more prone to phase separation. However, polypeptides are generally obtained by solid-phase synthesis, and the longer the sequence, the more costly it is, and therefore the need to form aggregates with extremely simple peptides contributes to the reduction of the cost of application of peptide aggregates. Existing short peptide coacervate systems include tetrapeptide coacervates (FFssFF), tripeptide coacervates (WKY), dipeptide coacervates (FF-OMe), and the like. However, short peptide aggregates remain without the limitations of solid phase synthesis. The development of amino acid aggregates can overcome this limitation, further reducing the cost of use. Disclosure of Invention The invention aims to provide an amino acid-based aggregate and a preparation method thereof. The invention solves the technical problem that the aggregate is difficult to prepare by single amino acid, and prepares the amino acid-based aggregate by modifying hydrophobic groups by amino acid and regulating and controlling the pH window of the aggregate formed by the amino acid. The invention can effectively reduce the cost of delivering drugs by peptide aggregates, and the prepared amino acid-based aggregates can enrich hydrophobic drug molecules, have high encapsulation efficiency and drug loading capacity, and are low-cost and potential drug delivery carriers. The method for preparing the amino acid-based aggregate comprises the following steps of adding amino acid modified by a hydrophobic group into water, adjusting the pH value to dissolve the amino acid, and adjusting the pH value to a specific value. The amino acid modified by the hydrophobic group at least contains two hydrophobic groups; the hydrophobic group may be selected from C 1-C6 straight or branched alkyl, -CH 2 -Ar (Ar represents an aromatic group), C 1-C6 straight or branched alkoxy, -C (=O) -O-R (R is an aromatic group or C 1-C6 straight or branched alkyl group); the aryl group may specifically be a phenyl group; The aryl is a substituted or unsubstituted aryl, and the substituent in the substituted aryl can be at least one of hydroxyl, amino, C 1-C6 straight-chain or branched-chain alkyl and C 1-C6 straight-chain or branched-chain alkoxy; Further, the two hydrophobic groups are each independently selected from at least one of Bn, cbz, boc, tBu, iPr, OMe; The amino acid may specifically be glycine. Specifically, the hydrophobic group modified amino acid is at least one of the following compounds: Wherein, the 、、、。 The hydrophobic group modifies the amino group in the amino acid, so that the pH window of the formed aggregate is acidic (pH is less than 7); the hydrophobic group is modified at the carboxyl end of the amino acid, so that the pH window of the formed aggregate is alkaline (pH is more than 7); Modification of both amino and carboxyl groups with hydrophobic groups results in the formation of aggregates both in acidic and basic conditions, i.e., the pH window for the aggregates is 1-14. If the amino acid modified by the hydrophobic group is Boc-G (-Bn), the pH window of the formed aggregate is 1.0-3.8; the amino acid modified by the hydrophobic group is G (-Bn) -tBu, and the pH window for forming a coacervate is 7.6-13.0; The amino acid modified by the hydrophobic group is Boc-G (-Bn) -Bn, and the pH window of the formed aggregate is 1.0-13.0; The amino acid modified by the hydrophobic group is Boc-G (-Bn-OH) -Bn,