A preparation method of intelligent targeted drug-loaded composite micelles

Abstract

The invention discloses a method for preparing intelligent target medicine carrying composite micelles. The surfaces of the composite micelles are modified by target ligands and pH / temperature synergy sensitive polymers at the same time; and reversible transformation between the shielding state of the target ligands during blood circulation (the temperature is 37 DEG C, and the pH value is 7.4) and the deshielding state of the target ligands in tumor tissues (the thermal therapy temperature ranges from 40 DEG C to 44 DEG C, and the pH value ranges from 6.5 to 6.8) is achieved. The pH and temperature dual sensitivities used in the method have the synergy; and the method is more suitable for the complex physiological environment of the human body. The method has the beneficial effects that targeting of the target ligands and the sensitive phase transformation characters of the pH / temperature synergy sensitive polymers are sufficiently used; and a target reversible shielding nanometer drug delivery system with the tumor targeted specificity and the blood circulation stability is built.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a preparation method of intelligent targeting drug-loaded composite micelles. Background technique [0002] The targeted nano drug delivery system can deliver the entrapped "drug" to the lesion at a fixed point, improve the specific therapeutic effect on tumor tissue, and reduce the side effects of chemotherapy drugs. However, most of the currently widely used targeting ligands are hydrophobic and exogenous, resulting in the targeted nano-drug delivery system being easily cleared by the mononuclear phagocytic system (MPS), reducing the accumulation of drugs in the tumor area. Realizing the shielding state of the targeting ligand in the blood circulation environment and the unshielding state in the tumor environment can effectively prevent the nano drug delivery system from being cleared by the mononuclear phagocytic system (MPS) and improve the tumor cell target of the nano d...

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Problems solved by technology

Salmaso et al. and Park et al. use temperature-sensitive polymer poly-N-isopropylacrylamide for controllable cellular uptake mediated by temperature-sensitive control of fusogenic proteins of gold nanoparticles or quantum dots, see Mastrotto F, Caliceti P , Amendola V, Bersani S, Magnusson JP, Meneghetti M, et al. Polymer control of ligand display on gold nanoparticles for multimodalswitchable cell targeting. Chem Commun 2011;47:9846–9848. and Kim C, Lee Y, Kim JS, Jeong JH, Park TG. Thermally triggered cellular uptake of quantum dotsimmobilized with poly(N-isopropylacrylamide) and cell penetrating peptide. Langmuir2010; 26:14965–1499. The temperature of the tumor site under mild hyperthermia is between 40-44℃, and the normal temperature of the human body is 37 ℃, according to which the researchers used methods such as copolymerization of hydrophilic monomers and N-isopropylacrylamide (see literature LiW, Li J, Gao J, Li B, Xia Y, Meng Y, et al. The fine-tuning of thermosensitive and degradable polymer micelles for enhancing intracellular uptake and drug release in tumors.Biomaterials2011; 32:3832-3844), improve the minimum critical solution temperature of the thermosensitive system to about 40°C, so as to realize the reversible shielding of the targeting ligand under mild hyperthermia and de-shielding transition, but this single use of temperature-sensitive reversible phase transition to achieve polymer stretching and shrinkage changes is not good, and the response speed is slow (see literature Lutz J-FF, Akdemir, Hoth A, Akdemir O.Point by point comparison of two thermosensitive polymers exhibiting a similar LCST: Is the age of poly(NIPAM) over? J Am Chem Soc 2006; 128:13046–13047.), difficult to apply in complex human physiological environment

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