Nanogel and nanogel drug carrier system both with smart response to tumor microenvironment

Abstract

The invention provides a nanogel with hydrophilic and hydrophobic reversal, charge reversal and intracellular redox responsiveness on the basis of pH regulation. The nanogel is prepared by cross-linking of thermo-sensitive monomer with controllable radical polymerization, amphoteric ionic monomer and amido-containing pH sensitive monomer through a disulfide-bond-containing cross-linking agent. The invention further provides a nanogel drug carrier system with smart response to tumor microenvironment and its preparation method. On the condition of blood pH 7.4, the nanogel is in a hydrophilic swelling state that is favorable for avoiding being phagocytosed by the reticuloendothelial system (RES) and accordingly, the nanogel has blood long circulation capacity; on the condition of tumor tissue subacidity, the state of the nanogel is reversed into a hydrophobic shrinking state that is favorable for the nanogel to realize effective concentration, depth penetration and be absorbed effectively by tumor cells on the tumor location. Besides, in the intracellular lysosome environment, negative charge of the nanogel is reversed into positive charge, which is favorable for the nanogel to escape from the lysosome; and then the nanogel releases drugs responsively in cytoplasm high-GSH environment, thereby achieving a good tumor inhibition effect.

Description

technical field [0001] The invention relates to the technical field of polymer drug carriers, in particular to a nanogel and a nanogel drug-carrying system that respond intelligently to the tumor microenvironment with pH-regulated hydrophilicity-hydrophobicity reversal, charge reversal, and intracellular redox responsiveness. and their preparation methods. Background technique [0002] Nano-drug delivery system is widely used in tumor therapy because of its EPR effect, which can improve tumor targeting, enhance the efficacy of chemotherapy drugs and reduce side effects. The anti-tumor nano-drug delivery system needs to pass through multiple physiological barriers in the body when reaching the target site through intravenous injection. In order to break through these physiological barriers, the ideal nano-drug delivery system must have long circulation in the blood, effective enrichment of tumor sites, deep tumor penetration, The ability to be effectively taken up by tumor c...

AI Technical Summary

Problems solved by technology

At present, the main strategy of hydrophilic-hydrophobic inversion nanomaterials is to rely on the fragmentation of pH-responsive chains to de-PEGylate, and the occurrence of such chemical reactions takes a lot of time, which leads to slow pH responsiveness and affects the anti-tumor effect of nano-medicines.

At the same time, the introduction of pH sensitivity not only requires a complicated chemical synthesis process, but also this process will introduce organic reagents, which may cause side effects

[0004] Due to the highly disordered vascular structure of tumor tissue, high interstitial fluid pressure and dense extracellular matrix, nanomedicines are found to be mainly enriched near tumor blood vessels, making it difficult to penetrate deep into tumor tissues, which greatly hinders its anti-tumor effect

At present, many literatures have reported the influence of nano-characteristics, such as particle size and surface potential, on the penetration of nano-drugs into tumor tissue, but how the hydrophilicity and hydrophobicity of nano-drugs affect their ability to penetrate deep into tumor tissue has not been reported.

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