Degradable acid-sensitive macromolecular amphipathic cationic block copolymers and micellar particles and preparation method thereof

A block copolymer, cationic technology, applied in the fields of pharmacy, biomedical engineering, and polymer chemistry, to achieve good synergy, excellent biodegradability, and promote progress

Inactive Publication Date: 2012-06-27
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This kind of acid-responsive cationic dual carrier has not been reported in the literature, and it has imp

Method used

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  • Degradable acid-sensitive macromolecular amphipathic cationic block copolymers and micellar particles and preparation method thereof
  • Degradable acid-sensitive macromolecular amphipathic cationic block copolymers and micellar particles and preparation method thereof
  • Degradable acid-sensitive macromolecular amphipathic cationic block copolymers and micellar particles and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Preparation of Biodegradable Acid Sensitive Amphiphilic Cationic Block Copolymers

[0039] 1. Preparation of amphiphilic block copolymers:

[0040] 1.1 Preparation of L-type amino acid benzyl ester N-carboxylic acid anhydride Take benzyl aspartate N-carboxylic acid anhydride as an example (BLA-NCA):

[0041] 25.0 g (0.11 mol) benzyl β-aspartate was suspended in 150 mL of dry THF, under argon protection, and heated to 40 °C. 13.5 g (0.045 mol) trimeric phosgene was dissolved in 25 mL of THF Then slowly add it dropwise into the reaction flask. After the reaction solution became clear, the reaction was continued for another 1 hour. Argon flow was bubbled for 30 minutes to remove the generated HCl. The reaction solution was filtered to remove a small amount of unreacted benzyl ester, then concentrated under reduced pressure to 50 mL, precipitated into a large amount of n-hexane (THF / hexane: 1 / 3), and recrystallized the initial product BLA-NCA in THF / hexane mixed solven...

Embodiment 2

[0056] Preparation of polymeric nanocarriers

[0057] 2.1 PLL(z) 10 - b -PAsp(DIP) 32 - Preparation of Ac polymer blank micelles

[0058] Dissolve 10 mg of polymer in 1 ml of DMSO / THF mixed solvent, stir thoroughly, add 0.5 mL of triethylamine to deprotonate the primary amino groups in the polylysine block, slowly drop to 10 mL of pH 7.4 In PBS solution. The micellar solution was dialyzed against PBS for 12 h and freeze-dried. Filter through a 0.45 μm aqueous phase filter, concentrate in an ultrafiltration centrifuge tube to 10 mL, that is, the polymer concentration is 1 mg / mL, and store in a refrigerator at 4 °C for later use.

[0059] 2.2 Loaded DOX polymer PLL(z) 10 - b -P Asp(DIP) 32 - Preparation of Ac micelles

[0060]2 mg water-soluble DOX was dissolved in 1 mL DMSO / THF mixed solvent, and 0.5 mL triethylamine was added to make DOX deprotonated from hydrophilic to hydrophobic; 10 mg polymer was dissolved in 1 mL DMSO / THF mixed solvent , add 0.5 mL triethylamine...

Embodiment 3

[0064] 3.1 Measurement of nanometer drug-loaded micelles particle size

[0065] The resulting 1 mg / mL polymer blank micelle solution was measured by dynamic light scattering method for its particle size PLL 34 - b -PAsp(DIP) 12 and PLL 10 - b -PAsp(DIP) 11 The average particle diameters of the prepared micelles were 38.0 nm and 40.0 nm, respectively.

[0066] 3.2 Determination of critical micelle concentration

[0067] Prepare pyrene into 3.0×10-4 M benzene solution, weigh a certain amount of polymer after the benzene volatilizes, use pH 7.4 PBS solution to constant volume, and then prepare 0.1-1000 ug / ml polymer and pyrene aqueous solution. Each sample was sonicated for 30 minutes at low intensity to promote the inclusion of pyrene into hydrophobic micelles, and then its fluorescence intensity was detected.

[0068] 3.3 Measurement of fluorescence spectrum

[0069] Polymer PLL(z) that will load DOX 10 - b -PAsp(DIP) 32 -Ac micellar solutions were adjusted to pH 5...

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Abstract

The invention discloses degradable acid-sensitive macromolecular amphipathic cationic block copolymers and micellar particles and a preparation method thereof. The hydrophilic/hydrophobic segments of the macromolecular amphipathic block copolymers disclosed by the invention are respectively formed by polylysines and polyaspartic derivatives with acid-sensitive groups. The preparation method of the macromolecular amphipathic block copolymers disclosed by the invention comprises the following steps of: using a micromolecular amine initiator for initiating the ring opening polymerization of N-carboxylic anhydrides of L-amino benzyl esters with active side groups; interconnecting the hydrophilic and hydrophobic segments by click chemistry; introducing the acid-sensitive groups by further ammonolysis reaction; and taking off benzyl blocking groups under acidic conditions to obtain a target product. The copolymers disclosed by the invention have excellent acid sensitivity, biocompatibility and biodegradability and can self-assemble and form nanoscale micelles in an aqueous solution, and the micelles can simultaneously load anti-cancer drugs, such as doxorubicin, and groups, such as BCL-2siRNA and can realize the intelligent controlled release of loads at tumor positions.

Description

[0001] technical field [0002] The invention relates to the fields of polymer chemistry, pharmacy and biomedical engineering, in particular to a degradable acid-sensitive polymer amphiphilic cationic block copolymer and micellar particles and a preparation method thereof. Background technique [0003] Multidrug resistance (MDR) is one of the main causes of chemotherapy failure in current cancer treatment. Multidrug resistance refers to the phenomenon of broad-spectrum drug resistance in which tumor cells develop cross-resistance to a drug that has nothing to do with it and has a completely different mechanism of action. [0004] Because the causes of multidrug resistance of tumor cells are complex, usually involving multiple factors and abnormalities of multiple genes, it is difficult to effectively reverse tumor cell resistance if only a single mode of multidrug resistance modulator or immunotherapy is used. multidrug resistance. In order to improve the efficacy of chemo...

Claims

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Application Information

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IPC IPC(8): C08G81/00C08G69/48C08G69/08A61K9/00A61K47/34A61K48/00
Inventor 帅心涛国翠平林树东王小莺陈伟才程度
Owner SUN YAT SEN UNIV
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