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A preparation method of intelligent targeted drug-loaded composite micelles

A composite micelle and targeted technology, applied in the field of biomedicine, can solve the problems of poor reversibility and slow response speed, and achieve the effects of improving the sensitivity of phase transition, simple and accurate operation, and long-term blood circulation.

Inactive Publication Date: 2018-12-28
NANKAI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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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

Method used

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  • A preparation method of intelligent targeted drug-loaded composite micelles
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Examples

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Embodiment 1

[0040] A preparation method of intelligent targeted drug-loaded composite micelles, the intelligent targeted drug-loaded composite micelles use temperature-sensitive polymers to control the "shielding" and "unshielding" states of targeting ligands on the surface of nanoparticles, that is, the The targeting ligands on the surface of nanoparticles are in a "shielding" state during normal blood circulation, and when the tumor site is locally heated to 40-44°C, the targeting ligands on the surface of nanoparticles are in a "unshielding" state, thereby restoring The targeting ability of nanoparticles, the preparation method comprises the following steps:

[0041] (1) Synthesis of thermosensitive block copolymers, non-targeted amphiphilic block copolymers and targeted amphiphilic block copolymers

[0042] 1) Synthesis of non-targeting amphiphilic block copolymer polyethylene glycol-polyε-caprolactone (mPEG-b-PCL) by ring-opening polymerization (ROP)

[0043]Add 1 g of polyethylene ...

Embodiment 2

[0070] A method for preparing a temperature-sensitive targeting composite micelle that can be used in an in vivo temperature environment, the operation of preparing the composite micelle and the ELISA characterization are basically the same as in Example 1, except that the temperature-sensitive block copolymer used is Poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide)-b-polyε-caprolactone (P(NIPAAm-co-DMAAm)-b-PCL), its subcritical solution The temperature is adjusted to between 39-40°C, and the preparation route is as follows

[0071] 1) Ordinary free radical synthetic macromolecular initiator poly(N-isopropylacrylamide-N,N-dimethylacrylamide) P(NIPAAm-co-DMAAm)-OH

[0072] Chain transfer agent mercaptoethanol 0.230mmol, initiator azobisisobutylcyanide (AIBN) 0.08mmol, monomer N-isopropylacrylamide (NIPAAm) 2.3mmol and N,N-dimethylacrylamide (DMAAm) Put 1mmol in a 25mL single-necked round bottom flask, then add 2mL of anhydrous N,N-dimethylformamide (DMF) for anhydrous an...

Embodiment 3

[0077] A method for preparing targeted composite micelles that are sensitive to both temperature and pH. The operation of preparing composite micelles such as ELISA characterization and other operations is basically the same as in Example 1, except that the temperature-sensitive block copolymer used is polymer (N-isopropylacrylamide-co-acrylamide-co-acrylic acid)-b-polyε-caprolactone (P(NIPAAm-co-AAm-co-AA)-b-PCL), the lower critical temperature At the same time, it is regulated by pH and temperature. Considering the complex environment of the human body, using a variety of environmental stimuli to regulate the phase transition of the polymer will allow more precise regulation and thus have better clinical application prospects.

[0078] The preparation route of the pH / temperature synergy-sensitive block copolymer is shown below.

[0079] 1) Ordinary free radical synthetic macromolecular initiator poly(N-isopropylacrylamide-co-acrylamide-co-acrylic acid)P(NIPAAm-co-AAm-co-AA)-...

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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...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/107A61K47/34A61K47/32A61K31/704A61K31/337A61K31/4745A61P35/00
Inventor 袁直吴玉昆杨承玲赖全勇郭华王蔚
Owner NANKAI UNIV
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