Macrophage-mimic shape changeable nanomedicine retained in tumor for multimodal therapy of breast cancer

Brucine, a weak alkaline indole alkaloid, is one of the main bioactive and toxic constituents of Nux-vomica. Modern pharmacology studies and clinical practice demonstrate that brucine possesses wide pharmacological activities, such as anti-tumor, anti-inflammatory, analgesic, and the effects on cardiovascular system and nervous system, etc. However, its central nervous system toxicity severely limits its clinical application. Herein, the physicochemical properties, pharmacological activities, and toxicity of brucine were reviewed, and the novel strategies to address the toxicity issues were discussed, aiming to bring new insights into further research and application of this active component.

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Brucine: A Review of Phytochemistry, Pharmacology, and Toxicology.

Nanoparticles have been extensively investigated for targeted delivery of anticancer drugs. Since the folate receptor is universally over-expressed on the tumor cell membrane, folic acid is often used to modify the fate of nanoparticles in biologicals. To fabricate targetable nanoparticles, folic acid was conjugated to a pullulan backbone and poly(DL-lactide-co-glycolide) (PLGA) (abbreviated as FAPuLG) was conjugated. KB cells and NIH3T3-cell-bearing mice were prepared to prove folate receptor targeting of FAPuLG nanoparticles. Nanoparticles of FAPuLG copolymer that self-assembled in water were small with diameters <200 nm. Doxorubicin (DOX) as a model drug was incorporated into the FAPuLG nanoparticles that were used to treat folate receptor over-expressing KB human carcinoma cells. Fluorescence microscopy revealed that DOX-incorporated FAPuLG nanoparticles induced strong red fluorescence in the KB cells in the absence of folic acid. However, fluorescence intensity was decreased by blocking folate receptors. Antitumor activity of FAPuLG nanoparticles against KB cells in vitro was also decreased by blocking folate receptors. In animal study using near-infrared dye-conjugated FAPuLG nanoparticles, fluorescence intensity was significantly higher at KB solid tumor than that of NIH3T3. The results indicate that FAPuLG nanoparticles can target the folate receptor of tumor cells. FAPuLG nanoparticles are a promising candidate for active targeting of anticancer agents.

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Folic-acid-conjugated pullulan/poly(DL-lactide-co-glycolide) graft copolymer nanoparticles for folate-receptor-mediated drug delivery

Anticarcinogenic effect of brucine in diethylnitrosamine initiated and phenobarbital-promoted hepatocarcinogenesis in rats.

The application of nanotechnology to drug delivery systems for cancer therapy has progressively received great attention. The most heavily investigated approach is the development of nanoparticles ...

Development, optimization, and evaluation of PEGylated brucine-loaded PLGA nanoparticles.

Background
Hepatocellular carcinoma is difficult to diagnose early, and most patients are already in the late stages of the disease when they are admitted to hospital. The total 5-year survival rate is less than 5%. Recent studies have showed that brucine has a good anti-tumor effect, but high toxicity, poor water solubility, short half-life, narrow therapeutic window, and a toxic dose that is close to the therapeutic dose, which all limit its clinical application. This study evaluated the effects of brucine immuno-nanoparticles (BIN) on hepatocellular carcinoma.

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Anti-tumor effects of brucine immuno-nanoparticles on hepatocellular carcinoma.

In vitro and in vivo studies have demonstrated that brucine is able to inhibit the proliferation of liver cancer cells and growth of animal tumors, and may be a promising anticancer drug. However, high toxicity, poor water solubility, short half-life, narrow therapeutic window, and similar therapeutic and toxic doses limit its clinical application in the treatment of malignant tumors. In our previous study, brucine immuno-nanoparticles were successfully prepared and added to the culture medium of liver cancer SMMC-7721 cells, and the results indicated that the brucine immuno-nanoparticles were able to target the cell membrane of liver cancer SMMC-7721 cells and significantly inhibit the proliferation, adhesion, invasion and metastasis of SMMC-7721 cells. The aim of the present study was to investigate the antitumor effect of brucine immuno-nanoparticles in vivo by establishing an in situ transplanted liver cancer in nude mice. The results indicated that in vivo application of the brucine immuno-nanoparticles resulted in temporary liver and kidney damage, and significantly reduced the α-fetoprotein (AFP) secretion of tumor cells (Bru-NP-MAb vs. the other groups; P<0.05). The brucine concentration of tumor tissues in the brucine immuno-nanoparticles group was significantly increased compared with that of the brucine nanoparticles group (Bru-NP-MAb vs. Bru-NP group or brucine group; P<0.05). The brucine immuno-nanoparticles were able to inhibit tumor growth and cluster of differentiation 34 expression and angiogenesis of tumor tissues, and induce the apoptosis of tumor cells (Bru-NP-MAb vs. Bru-NP group or brucine group; P<0.05). In conclusion, as a novel type of targeted drug, brucine nanoparticles combined with anti-AFP monoclonal antibodies was more effective compared with brucine nanoparticles or brucine alone in inhibiting tumor growth via the enhancement of apoptosis, and the suppression of proliferation and angiogenesis in vivo. Therefore, the brucine immuno-nanoparticle is a promising targeted drug for the treatment of hepatocellular carcinoma.

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Antitumor effects of brucine immuno-nanoparticles on hepatocellular carcinoma in vivo

Preparation method of strychnine immune nanoparticles

The invention relates to brucine immune nanoparticles. The immune nanoparticle is characterized in that the brucine is taken as an active component, a carboxylation polyethylene glycol-a polylactic acid segmented copolymer is taken as a medicament coated auxiliary material, an antihuman AFP monoclonal antibody is linked outside the medicament coated auxiliary material to prepare immune-targeting nanoparticles. The brucine immune nanoparticles have the advantages of simple preparation technology, high entrapment rate, stable medicament release and good ballability, and is used for preparing antitumor immune-targeting medicines, the medicine is used for anti-liver cancer treatment, the antihuman AFPMcAb-polyethylene glycol-polylactic acid segmented copolymer nanometer carrier is capable of increasing the aggregation of brucine in liver cancer cells through peripheral intravenous administration, so that the medicine is locally and slowly released, the effect time of the medicine to tumorcells is prolonged, local medicine concentration is raised and the general toxic reaction of the brucine is reduced; and the brucine immune nanoparticles have the merits of precious targeting histiocytoma medicament aggregation, stable medicament release, good anticancer effect, safety and the like.

Brucine immune nanoparticles

The invention relates to a purpose of immunological nanoparticles of brucine in preparing anti-hepatoma target drugs. The immunological nanoparticles of brucine are immunological target nanoparticles which treat brucine as an active component and a carboxylated polyethylene glycol-polylactic acid segmented copolymer as a drug coating accessory, and are formed by externally linking with anti-humanAFP monoclonal antibodies. The immunological nanoparticles of brucine provided by the invention, which have the characteristics of simple technology, high entrapment rate, stable drug release, and good balling, can be used for preparing antitumor target drugs which can be used for anti-hepatoma treatment. By intravenous injection, a nanometer carrier anti-human AFPMcAb-polyethylene glycol-polylactic acid segmented copolymer allows brucine aggregation in hepatoma cells to be increased, the drugs to be slowly and locally released, the effect time of the drugs to tumor cells to be prolonged, thelocal drug concentration to be improved, and the whole body toxicity of brucine to be reduced. So the immunological nanoparticles of brucine of the present invention have the advantages of accurate aggregation of target drugs in the cells of tumor tissues, stable drug release, good anticancer effect, safety and the like.

Kepan Gao

Papers

Anti-tumor effects of brucine immuno-nanoparticles on hepatocellular carcinoma.

Antitumor effects of brucine immuno-nanoparticles on hepatocellular carcinoma in vivo

Preparation method of strychnine immune nanoparticles

Brucine immune nanoparticles

Purpose of immunological nanoparticles of brucine in preparing anti-hepatoma target drugs