Lycobetaine

A comparison study between lycobetaine-loaded nanoemulsion and liposome using nRGD as therapeutic adjuvant for lung cancer therapy.[Pubmed:28966099]

Eur J Pharm Sci. 2018 Jan 1;111:293-302.

To achieve tumor-selective drug delivery, various nanocarriers have been explored using either passive or active targeting strategies. Despite the great number of studies published annually in the field, only nanocarriers using approved excipients reach the clinical stage. In our study, two classic nanoscale formulations, nanoemulsion (NE) and liposome (Lipo) were selected for the encapsulation of Lycobetaine (LBT). To improve the lipid solubility of LBT, oleic acid (OA) was used to complex (LBT-OA) with Lycobetaine (LBT). Besides, PEGylated lecithin was used to enhance the circulation time. The release behaviors of LBT from non-PEGylated and PEGylated NE and Lipo were compared. PEGylated LBT-OA loaded Lipo (LBT-OA-PEG-Lipo) exhibited a sustained release rate pattern, and in vivo pharmacokinetic profiles showed the extended circulation compared nanoemlusions. Besides, LBT-OA-PEG-Lipo showed an enhanced anti-tumor effect in the mice xenograft lung carcinoma model. Moreover, a multi-target peptide nRGD was co-administered as a therapeutic adjuvant with LBT-OA loaded formulations, which demonstrated improved tumor penetration and enhanced extravasation of formulations. Also, co-administration of nRGD significantly improved the in vivo antitumor efficacy of different formulations, likely due to the depletion of tumor-associated macrophages (TAMs). Thus, LBT-OA-PEG-Lipo+nRGD may represent a promising strategy for cancer chemotherapy against lung carcinoma.

Inhibitions of several antineoplastic drugs on serum sialic Acid levels in mice bearing tumors.[Pubmed:23641340]

Sci Pharm. 2013 Jan-Mar;81(1):223-31.

Six murine tumors, including ascetic tumors HepA, EC, P388 leukemia, S180 and solid tumor S180, and Lewis lung carcinoma, were employed in this work. The free sialic acid concentrations in both blood and ascites were measured in tumor-bearing mice. The results showed that the content of sialic acids in blood was increased in tumor growth and certain tumor types. Higher sialic acid content was observed in ascites than that present in blood. The influence of antineoplastic agents (vincristine, thiotepa, adriamycin, probimane, cisplatin, oxalysine, cortisone, nitrogen mustard, Lycobetaine, Ara-C, harringtonine, and cyclophosphamide) on the content of sialic acids in mice blood bearing solid tumors of either S180 or Lewis lung carcinoma was observed. Different inhibitions of antineoplastic drugs on both tumor growth and serum sialic acid levels in mice bearing tumors were found. Among these antineoplastic drugs, probimane, cisplatin, nitrogen mustard, and Lycobetaine were able to decrease the serum sialic acid levels in mice bearing tumors. Since these four antineoplastic drugs are all DNA chelating agents, it was proposed that the inhibition of tumor sialic acids by these drugs might be through the DNA template via two ways. Since we have found no effect of antineoplastic drugs on serum sialic acid levels in normal mice, this suggests that the inhibition of antineoplastic drugs on sialic acids is by tumor involvement.

nRGD modified lycobetaine and octreotide combination delivery system to overcome multiple barriers and enhance anti-glioma efficacy.[Pubmed:28544965]

Colloids Surf B Biointerfaces. 2017 Aug 1;156:330-339.

For glioma as one of the most common and lethal primary brain tumors, the presence of BBB, BBTB, vasculogenic mimicry (VM) channels and tumor-associated macrophages (TAMs) are key biological barriers. Here, a novel drug delivery system which could efficiently deliver drugs to glioma by overcoming multi-barriers and increase antitumor efficacy through multi-therapeutic mechanisms was well developed. In this study, a multi-target peptide nRGD was used to transport across the BBB, mediate tumor penetration and target TAMs. Lycobetaine (LBT) was adopted to kill glioma cells and octreotide (OCT) was co-delivered to inhibit VM channels and prevent angiogenesis. LBT-OCT liposomes (LPs) showed controlled release profile in vitro, increased uptake efficiency, improved inhibitory effect against glioma cells and VM formation, and enhanced BBB-crossing capability. The median survival time of glioma-bearing mice administered with LBT-OCT LPs-nRGD was significantly longer than LBT-OCT LPs (P<0.01). Besides, nRGD achieved a stronger inhibitory effect against tumor associated macrophages (TAMs) compared to LPs-iRGD treatment groups in vivo. Thus, LPs-nRGD represented a promising versatile delivery platform for combination drug therapy in glioma treatment.

Analysis of Lycobetaine in Rat Plasma by LC-ESI-MS/MS.[Pubmed:27903551]

J Chromatogr Sci. 2017 Mar 1;55(3):301-308.

In this study, a selective and sensitive liquid chromatography-electrospray ionization-tandem mass spectrometric method was developed and validated for the determination of Lycobetaine in rat plasma. Berberine was selected as the internal standard, and rat plasma samples were pretreated via protein precipitation and further separated on a diamonsil octadecyl-silylated silica column using 0.2% (v/v) aqueous formic acid and methanol as the mobile phase. Selected reaction monitoring was performed using the transitions m/z 266.1 --> 208.1 and m/z 336.1 --> 320.0 to determine the concentrations of Lycobetaine and internal standard, respectively. The injection volume was 1 microL, and the calibration curve was linear (R2 = 0.9998), while the validated lower limit of quantification was 25 ng/mL. Precision varied from 3.4% to 9.9%, and accuracy varied from -2.6% to 8.7%. Lycobetaine remained stable under all relevant analytical conditions tested in the study. The method was successfully applied to determine the plasma concentration of Lycobetaine in a pharmacokinetic study. After intravenous administration of 10 mg/kg and oral administration of 200 mg/kg Lycobetaine in rats, the pharmacokinetic parameters were calculated and the oral bioavailability of Lycobetaine was determined as 7.30% +/- 1.44%.

Nanoemulsion loaded with lycobetaine-oleic acid ionic complex: physicochemical characteristics, in vitro, in vivo evaluation, and antitumor activity.[Pubmed:23723698]

Int J Nanomedicine. 2013;8:1959-73.

BACKGROUND: Intravenous injection of Lycobetaine was found to show significant cytotoxic activity against (inter alia) Lewis lung carcinoma, but its therapeutic use is largely limited due to an extremely short half-life in blood. This study aimed at developing a novel lipid nanocarrier-based formulation for Lycobetaine delivery. The formulation is feasible for scale-up production, exhibiting good parenteral acceptability and improved circulation characteristics. METHODS: To enhance its lipophilicity, oleic acid was selected to form ionic complexes with Lycobetaine (LBT). The nanoemulsion loaded with LBT-oleic acid complex (LBT-OA-nanoemulsion) and PEGylated LBT-OA-nanoemulsion (NE) (LBT-OA-PEG-NE) were prepared by a simple high-pressure homogenization method. RESULTS: A high-encapsulation efficiency of around 97.32% +/- 2.09% was obtained for LBT-OA-PEG-NE under optimized conditions. Furthermore, the in vivo pharmacokinetics and biodistribution of LBT-OA-NE, LBT-OA-PEG-NE, and free LBT were studied in rats. Free LBT and LBT-OA-PEG-NE displayed AUC0-10h (area under the concentration-time curve from 0 to 10 hours) of 112.99 mg/L*minute and 3452.09 mg/L*minute via intravenous administration (P < 0.005), respectively. Moreover, LBT-OA-PEG-NE showed significantly lower LBT concentration in the heart, liver, and kidney, while achieving higher concentration of LBT in the lung when compared to free LBT at the same time (P < 0.005). The LBT-OA-PEG-NE exhibited higher growth inhibitory effect and longer survival time than free LBT in both heterotopic and lung metastatic tumor models. CONCLUSION: These results demonstrated that LBT-OA-PEG-NE is an attractive parenteral formulation for cancer therapy.