Combination of micelles and liposomes as a promising drug delivery system: a review.

Among various nanocarriers, liposomes, and micelles are relatively mature drug delivery systems with the advantages of prolonging drug half-life, reducing toxicity, and improving efficacy. However, both have problems, such as poor stability and insufficient targeting. To further exploit the excellent properties of micelles and liposomes and avoid their shortcomings, researchers have developed new drug delivery systems by combining the two and making use of their respective advantages to achieve the goals of increasing the drug loading capacity, multiple targeting, and multiple drug delivery. The results have demonstrated that this new combination approach is a very promising delivery platform. In this paper, we review the combination strategies, preparation methods, and applications of micelles and liposomes to introduce the research progress, advantages, and challenges of composite carriers.

Progress in research and development of temozolomide brain-targeted preparations: a review.

Gliomas are a heterogeneous group of brain tumours with high malignancy, for which surgical resection remains the mainstay of treatment at present. However, the overall prognosis of gliomas remains poor because of their aggressiveness and high recurrence. Temozolomide (TMZ) has anti-proliferative and cytotoxic effects and is indicated for glioblastoma multiforme and recurrent mesenchymal astrocytoma. However, TMZ is disadvantaged by low efficacy and drug resistance, and therefore it is necessary to enhance the brain drug concentration of TMZ to improve its effectiveness and reduce the toxic and adverse effects from systemic administration. There have been many nano-formulations developed for the delivery of TMZ to gliomas that overcome the limitations of TMZ penetration to tumours and increase brain targeting. In this paper, we review the research progress of TMZ nano-formulations, and also discuss challenges and opportunities in the research and development of drug delivery systems, hoping that the data and information summarised herein could provide assistance for the clinical treatment of gliomas.

Preparation and characterization of paclitaxel palmitate albumin nanoparticles with high loading efficacy: an in vitro and in vivo anti-tumor study in mouse models.

BACKGROUND: Combination of the prodrug technique with an albumin nano drug-loaded system is a novel promising approach for cancer treatment. However, the long-lasting and far-reaching challenge for the treatment of cancers lies in how to construct the albumin nanometer drug delivery system with lead compounds and their derivatives. METHODS: In this study, we reported the preparation of injectable albumin nanoparticles (NPs) with a high and quantitative drug loading system based on the NabTM technology of paclitaxel palmitate (PTX-PA). RESULTS: Our experimental study on drug tissue distribution in vivo demonstrated that the paclitaxel palmitate albumin nanoparticles (Nab-PTX-PA) remained in the tumor for a longer time post-injection. Compared with saline and paclitaxel albumin nanoparticles (Abraxane®), intravenous injection of Nab-PTX-PA not only reduced the toxicity of the drug in normal organs, and increased the body weight of the animals but maintained sustained release of paclitaxel (PTX) in the tumor, thereby displaying an excellent antitumor activity. Blood routine analysis showed that Nab-PTX-PA had fewer adverse effects or less toxicity to the normal organs, and it inhibited tumor cell proliferation more effectively as compared with commercial paclitaxel albumin nanoparticles. CONCLUSIONS: This carrier strategy for small molecule drugs is based on naturally evolved interactions between long-chain fatty acids (LCFAs) and Human Serum Albumin (HSA), demonstrated here for PTX. Nab-PTX-PA shows higher antitumor efficacy in vivo in breast cancer models. On the whole, this novel injectable Nab-PTX-PA has great potential as an effective drug delivery system in the treatment of breast cancer.

A Novel Drug Delivery Carrier Comprised of Nimodipine Drug Solution and a Nanoemulsion: Preparation, Characterization, in vitro, and in vivo Studies.

PURPOSE: Nimodipine (NIMO) is used clinically to treat ischemic damage resulting from subarachnoid hemorrhage. However, clinical application of NIMO is limited by poor aqueous solubility and low safety. To overcome these limitations, a novel two-vial NIMO-loaded nanoemulsion (NIMO-TNE) was designed in this study. METHODS: NIMO-TNE was prepared by mixing a nimodipine-polyethylene glycol 400 (NIMO-PEG400) solution and a commercially available 20% injectable blank nanoemulsion (BNE). Drug distribution in NIMO-TNE, physical stability, and dilution stability were evaluated in vitro, and pharmacokinetics and pharmacodynamics were evaluated in vivo. Safety was assessed using the hemolysis test and the intravenous irritation test, and acute toxicity of NIMO-TNE was compared with that of commercial Nimotop injection. RESULTS: Drug loading (DL) in NIMO-TNE was enhanced 5-fold compared with that in Nimotop injection. The mean particle size of NIMO-TNE was 241.53 ± 1.48 nm. NIMO-TNE and NIMO-TNE diluted in 5% glucose injection and 0.9% sodium chloride was stable for a sufficient duration to allow for clinical use. In addition, NIMO-TNE exhibited a similar pharmacokinetic profile and similar brain ischemia reduction in a rat middle cerebral artery occlusion (MCAO) model compared to Nimotop injection. Furthermore, NIMO-TNE did not induce hemolysis at 37°C, and NIMO-TNE induced less intravenous irritation than Nimotop injection. Moreover, NIMO-TNE could be injected at a 23-fold higher dose than the LD50 of Nimotop injection with no obvious toxicity or side effects. CONCLUSION: NIMO-TNE is a promising formulation suitable for intravenous injection, is easy to prepare, and exhibits excellent safety.

Study on the cellular internalization mechanisms and in vivo anti-bone metastasis prostate cancer efficiency of the peptide T7-modified polypeptide nanoparticles.

Bone-metastasis prostate cancer (BMPCa)-targeting gene therapy is gaining increasing concern in recent years. The peptide T7-modified polypeptide nanoparticles for delivery DNA (CRD-PEG-T7/pPMEPA1) was prepared as our previous study. However, the feasibility of CRD-PEG-T7/pPMEPA1 for BMPCa treatment, the mechanisms underlying cellular uptake, anti-BMPCa effect, and administration safety requires further research. LNCaP cells treated with endocytosis inhibitors and excessive T7 under different culture condition were carried out to investigate the mechanisms of cellular uptake of the CRD-PEG-T7-pPMEPA1. A transwell assay was applied to evaluate the cell migration ability. Besides, the tumor volume and survival rates of the PCa xenograft mice model were recorded to estimate the anti-tumor effect. In addition, the weight profiles of the PCa tumor-bearing mice, the blood chemistry, and the HE analysis of visceral organs and tumor was conducted to investigate the administration safety of CRD-PEG-T7/pPMEPA1. The results showed that PCa cellular uptake was decreased after treating with excessive free T7, endocytosis inhibitors and lower incubation temperature. Besides, CRD-PEG-T7/pPMEPA1 could inhibit the LNCaP cells chemotaxis and tumor growth. In addition, the survival duration of the PCa tumor-bearing mice treating with CRD-PEG-T7/pPMEPA1 was significantly prolonged with any systemic toxicity or damage to the organs. In conclusion, this research proposes a promising stratagem for treatment BMPCa by providing the biocompatible and effective carrier for delivery DNA therapeutic agents.

Development Of Novel Liposome-Encapsulated Combretastatin A4 Acylated Derivatives: Prodrug Approach For Improving Antitumor Efficacy.

PURPOSE: The objective of the present study was to develop a liposomal drug delivery system based on combretastatin A4 (CA4) prodrugs modified with varying alkyl chains and investigate the in vitro drug conversion from prodrug and in vivo antitumor effect. METHODS: The prodrug of CA4 was synthesized with stearyl chloride (18-carbon chain), palmitoyl chloride (16-carbon chain), myristoyl chloride (14-carbon chain), decanoyl chloride (10-carbon chain), and hexanoyl chloride (6-carbon chain) at the 3'-position of the CA4. Subsequently, it was encapsulated with liposomes through the thin-film evaporation method. Furthermore, the characteristics of prodrug-liposome were evaluated using in vitro drug release, conversion, and cytotoxicity assays, as well as in vivo pharmacokinetic, antitumor, and biodistribution studies. RESULTS: The liposome system with loaded CA4 derivatives was successfully developed with nano-size and electronegative particles. The rate of in vitro drug release and conversion was reduced as the fatty acid carbon chain lengthened. On the contrary, in vivo antitumor effects were improved with the enlargement of the fatty acid carbon chain. The results of the in vivo pharmacokinetic and tissue distribution studies indicated that the reduced rate of CA4 release with a long carbon chain could prolong the circulation time and increase the drug concentration in the tumor tissue. CONCLUSION: These results suggested that the release or hydrolysis of the parent drug from the prodrug was closely related with the in vitro and in vivo properties. The slow drug release of CA4 modified with longer acyl chain could prolong the circulation time and increase the concentration of the drug in the tumor tissue. These effects play a critical role in increasing the antitumor efficacy.

Development and validation of an UPLC-UV method for determination of a novel triazine coccidiostat ethanamizuril and its metabolite M3 in chicken tissues.

Ethanamizuril (EZL) is a novel anti-coccidial triazine synthesized by the Shanghai Veterinary Research Institute of the Chinese Academy of Agricultural Sciences. As a novel coccidiostat, it is essential to study its residue in food animal tissues. In this study, a reliable UPLC method for the determination of ethanamizuril (EZL) and one of its metabolites (M3) in chicken muscle, skin and fat, liver, and kidney samples was developed. Analytes were extracted using acetonitrile and 10% sodium carbonate solution, defatted by n-hexane, and further purified by using an Oasis MCX cartridge. The calibration curves for both test compounds were linear in all tissue matrices we tested: muscle, skin and fat, liver and kidney. The mean relative recoveries of EZL and M3 were from 87.3% to 103.2% between all tissue samples. The inter-day and intra-day relative standard deviations were within 15% and 20%, respectively. This method is accurate, reproducible and is ready to be field-tested.

[Separation and Quantitative Determination of Four Flavonoids in Tetrastigma hemsleyanum].

OBJECTIVE: To develop a method for separation and quantitative determination of four flavonoids in Tetrastigma hemsleyanum. METHODS: The Separation was performed on a Waters Preparative scale LC-MS autopurification system. Several spectral analyses, such as NMR,HR-MS and UV were used to identify the chemical structures. Quantitative assay was performed on a UHPLC Phenomenex Kinetex C18 column (100 mm x 4.6 mm, 2.6 µm) with the mobile phase consisting of acetonitrile( B) and water containing 0. 1% formic acid (A) in a gradient mode at a flow rate of 0.4 mL/min. The column temperature was at 30 °C and the optimum detection wavelength of DAD was set at 350 nm. RESULTS: Four flavonoids were isolated from the root of Tetrastigma hemsleyanum, which were identified as rutin, isoquercitrin, kaempferol-3-O-rutinoside and astragalin. As to quantitative analysis, a good separation of four flavonoids with in 17.5 min, the linear range of rutin, isoquercitrin, kaempferol-3-O-rutinoside and astragalin was 0.283-11.32 µg/mL (r1 = 0.9998), 0.311-12.44 µg/mL (r2 = 0.9994), 0.277-11.08 µg/mL (r3 = 0.9995) and 0.103-2.06 µg/mL (r4 = 0.9990), respectively. The average recovery (n = 6) was 99.75% (RSD = 2.15%), 98.73% (RSD = 2.58%) ,98. 03% (RSD = 2.23%), and 97.62% (RSD = 1.95%), respectively. CONCLUSION: Four flavonoids are isolated from the root of Tetrastigma hemsleyanum for the first time, and the UHPLC method is simple, rapid and accurate, which can be used for quantitative analysis of multi-component of Tetrastigma hemsleyanum and provide a novel approach for evaluation of the quality of Tetrastigma hemsleyanum comprehensively.