CN-117304350-B - Hydroxyalkyl starch-photosensitizer macromolecular compound coated with anthraquinone drug, nano drug-loading system, preparation and application thereof

Abstract

The invention belongs to the technical field of multidisciplinary intersection of chemistry, pharmacy, medicine and the like, and particularly relates to a hydroxyalkyl starch-photosensitizer macromolecular compound for encapsulating anthraquinone medicaments, a nano medicament carrying system and preparation and application thereof. The hydrophilic end of the macromolecular compound is hydroxyalkyl starch, and the hydrophobic end is hydrophobic organic cyanine dye molecule. According to the invention, the hydrophobic organic cyanine dye molecular photosensitizer with photodynamic and photoivelopment characteristics is used as a hydrophobic end, and after being coupled with hydroxyalkyl starch, the constructed amphiphilic macromolecule can maintain the stability of the original photosensitizer and improve the water solubility of the original photosensitizer. And the ultraviolet-visible light absorption peak can be optimized to match the 660nm near infrared laser irradiation used for photodynamic therapy. The oil-in-water nano system constructed by the emulsification method can also keep the photodynamic and photoimaging characteristics of the photosensitizer, and successfully encapsulate the hydrophobic antitumor drug and realize the combined treatment of tumor targeting while improving the biocompatibility of the photosensitizer.

Inventors

• LI ZIFU
• YANG XIANGLIANG
• YONG ZHENGTAO

Assignees

• 华中科技大学

Dates

Publication Date

20260505

Application Date

20230928

Claims (5)

1. 1. A preparation method of an amphiphilic macromolecular compound coupled by hydroxyalkyl starch and a photosensitizer is characterized in that the macromolecular compound is obtained by coupling hydroxyalkyl starch and the photosensitizer through a chemical bond, wherein the hydroxyalkyl starch in the amphiphilic macromolecular compound is used as a hydrophilic end, the photosensitizer is used as a hydrophobic end, the photosensitizer is a hydrophobic organic cyanine dye molecule, the hydrophobic organic cyanine dye molecule is one or more of IR820, IR780, IR808, IR783 and IR825, the chemical bond is an amide bond or an ester bond, and the preparation method comprises the following steps: (1) The hydroxy in the hydroxyalkyl starch is substituted by chlorine atoms in a compound containing at least one acyl chloride and nitro to obtain the hydroxyalkyl starch containing ketone carbonyl and nitro; (2) The hydroxyalkyl starch containing ketone carbonyl and nitro is subjected to substitution reaction with a primary amine compound containing at least two amino groups, so that the hydroxyalkyl starch containing amino groups is obtained when the ketone carbonyl is substituted into an amide bond; (3) And carrying out substitution reaction on the hydroxyalkyl starch containing amino and chlorine atoms contained in the photosensitizer to obtain the amphiphilic macromolecular compound coupled with the hydroxyalkyl starch and the photosensitizer.
2. 2. The method of claim 1, wherein the photosensitizer is IR820, and wherein the IR820 is coupled to the hydroxyalkyl starch via an amide linkage.
3. 3. The nanometer medicine carrying system based on the amphiphilic macromolecular compound is characterized by comprising the amphiphilic macromolecular compound prepared by the preparation method of claim 1 or 2 and further comprising anthraquinone antitumor medicines, wherein the anthraquinone antitumor medicines are physcion.
4. 4. The nano drug delivery system of claim 3, wherein the anthraquinone anti-tumor drug and the amphiphilic macromolecular compound are constructed into nano particles of an oil-in-water system by a ultrasonic emulsification method, wherein the anthraquinone anti-tumor drug is used as an oil phase, and the amphiphilic macromolecular compound is used as an aqueous phase.
5. 5. An antitumor drug comprising the nanodrug delivery system of claim 3 or 4 and a pharmaceutically acceptable additive.

Description

Hydroxyalkyl starch-photosensitizer macromolecular compound coated with anthraquinone drug, nano drug-loading system, preparation and application thereof Technical Field The invention belongs to the technical field of multidisciplinary intersection of chemistry, pharmacy, medicine and the like, and particularly relates to a hydroxyalkyl starch-photosensitizer macromolecular compound for encapsulating anthraquinone medicaments, a nano medicament carrying system and preparation and application thereof. Background Photodynamic therapy (Photodynamic therapy, PDT) is a therapeutic strategy in which energy in laser light is transferred to surrounding oxygen molecules by photosensitizing agents, resulting in elevated levels of intracellular reactive oxygen species (Reactive oxygen species, ROS), thereby dying tumor cells from oxidative damage that is difficult to repair in time. Compared with the traditional therapy, the photodynamic therapy has the advantages of small side effect, short treatment time, simple operation, good killing effect and the like, so that the photodynamic therapy has more and more clinical application. The cyanine near infrared fluorescent dye such as IR820 has excellent biological safety and good curative effect, and is very suitable for photodynamic therapy. However, single photosensitizer small molecules have poor solubility, cannot realize long circulation in vivo, lack tumor targeting, and are extremely easy to be metabolized by liver and kidney. Therefore, it is urgent to explore a novel material loaded with a small molecule photosensitizer. Moreover, accumulation of ROS alone is not sufficient to achieve broad and efficient killing of tumor cells. Since the Pentose Phosphate Pathway (PPP) serves as a branch of glycolysis of cells, it takes on the task of supplying NADPH (reduced coenzyme II) and is able to maintain the antioxidant system of tumor cells. The physcion (Physcion) is anthraquinone compound, and early researches show that the physcion has the effects of inducing apoptosis of tumor cells, destroying cell cycle, inhibiting tumor metastasis and the like, and has stronger anti-tumor activity. However, due to its water solubility, physcion has been difficult to be applied clinically in the field of tumor treatment. Indeed, it is difficult to achieve an ideal therapeutic effect by single chemotherapy or photodynamic therapy, but the therapeutic effect of the tumor can be remarkably improved by adopting a combined therapy method, and the occurrence and development of the tumor can be inhibited from multiple aspects by a strategy of combining photodynamic therapy with a chemotherapeutic drug. The cyanine photosensitizer and the anthraquinone drug have poor water solubility and low biocompatibility, so that the clinical application of the cyanine photosensitizer and the anthraquinone drug is limited. Therefore, how to realize the co-loading of two components while improving the targeting and accumulation of the tumor of the medicine is a technical problem which needs to be solved in the field. Disclosure of Invention Aiming at the defects of the prior art, the invention provides a hydroxyalkyl starch-photosensitizer coupled macromolecular compound for encapsulating anthraquinone drugs, a nano drug delivery system, a preparation method and application thereof. The photosensitizer with light response treatment characteristic is used as the hydrophobic end of a macromolecular compound, is coupled with hydrophilic hydroxyalkyl starch, and encapsulates the hydrophobic antitumor anthraquinone drug into nanoparticles through ultrasonic emulsification, so that the problem that the cyanine photosensitizer and the anthraquinone drug are poor in biocompatibility and poor in targeting property and the like, and the curative effect is poor is solved. The invention provides an amphiphilic macromolecular compound coupled by hydroxyalkyl starch and a photosensitizer, wherein the macromolecular compound is obtained by coupling the hydroxyalkyl starch and the photosensitizer through chemical bonds, the hydroxyalkyl starch in the amphiphilic macromolecular compound is used as a hydrophilic end, the photosensitizer is used as a hydrophobic end, and the photosensitizer is a hydrophobic organic cyanine dye molecule. Preferably, the hydrophobic organic cyanine dye molecule is one or more of IR820, IR780, IR808, IR783 and IR825, and the chemical bond is an amide bond or an ester bond. Further preferably, the photosensitizer is IR820, the IR820 and the hydroxyalkyl starch being coupled by an amide bond. According to another aspect of the present invention, there is provided a method for preparing the amphiphilic macromolecular compound, comprising the steps of: (1) Hydroxy in hydroxyalkyl starch is substituted by chlorine atom in compound containing at least one acyl chloride and nitro to obtain hydroxyalkyl starch containing ketone carbonyl and nitro; (2) The hydroxyalkyl starch containing ketone carbony