Thermo-Sensitive Liposome co-Loaded of Vincristine and Doxorubicin Based on Their Similar Physicochemical Properties had Synergism on Tumor Treatment.

PURPOSE: To develop vincristine (VCR) and doxorubicin (DOX) co-encapsulated thermo-sensitive liposomes (VD-TSL) against drug resistance, with increased tumor inhibition rate and decreased system toxicity, improving drug targeting efficiency upon mild hyperthermia (HT) in solid tumor. METHODS: Based on similar physicochemical properties, VCR and DOX were co-loaded in TSL with pH gradient active loading method and characterized. The time-dependent drug release profiles at 37 and 42°C were assessed by HPLC. Then we analysed the phospholipids in filtrate after ultrafiltration and studied VD-TSL stability in mimic in vivo conditions and long-time storage conditions (4°C and -20°C). Cytotoxic effect was studied on PANC and sw-620 using MTT. Intracellular drug delivery was studied by confocal microscopy on HT-1080. In vivo imaging of TSL pharmacokinetic and biodistribution was performed on MCF-7 tumor-bearing nude mice. And therapeutic efficacy on these xenograft models were followed under HT. RESULTS: VD-TSL had excellent particle distribution (about 90 nm), high entrapment efficiency (>95%), obvious thermo-sensitive property, and good stability. MTT proved VD-TSL had strongest cell lethality compared with other formulations. Confocal microscopy demonstrated specific accumulation of drugs in tumor cells. In vivo imaging proved the targeting efficiency of TSL under hyperthermia. Then therapeutic efficacy revealed synergism of VCR and DOX co-loaded in TSL, together with HT. CONCLUSION: VD-TSL could increase drug efficacy and decrease system toxicity, by making good use of synergism of VCR and DOX, as well as high targeting efficiency of TSL.

[Current status and prospect of translational medicine in nanotechnology].

Nowadays, nanotechnologies have shown wide application foreground in the biomedical field of medicine laboratory tests, drug delivery, gene therapy and bioremediation. However, in recent years, nanomaterials have been labeled poisonous, because of the disputes and misunderstandings of mainstream views on their safety. Besides, for the barriers of technical issues in preparation like: (1) low efficacy (poor PK & PD and low drug loading), (2) high cost (irreproducibility and difficulty in scale up), little of that research has been successfully translated into commercial products. Currently, along with the new theory of "physical damage is the origin of nanotoxicity", biodegradability and biocompatibility of nanomaterials are listed as the basic principle of safe application of nanomaterials. Combining scientific design based on molecular level with precision control of process engineering will provide a new strategy to overcome the core technical challenges. New turning point of translational medicine in nanotechnology may emerge.

A novel preparative method for nanoparticle albumin-bound paclitaxel with high drug loading and its evaluation both in vitro and in vivo.

We developed a novel preparative method for nanoparticle albumin-bound (nab) paclitaxel with high drug loading, which was based on improved paclitaxel solubility in polyethylene glycol (PEG) and self-assembly of paclitaxel in PEG with albumin powders into nanoparticles. That is, paclitaxel and PEG were firstly dissolved in ethanol, which was subsequently evaporated under vacuum. The obtained liquid was then mixed with human serum albumin powders. Thereafter, the mixtures were added into phosphate-buffered saline and nab paclitaxel suspensions emerged after ultrasound. Nab paclitaxel was finally acquired after dialysis and freeze drying. The drug loading of about 15% (W/V) were realized in self-made nab paclitaxel, which was increased by approximately 50% compared to 10% (W/V) in Abraxane. Now this new preparative method has been authorized to obtain patent from China and Japan. The similar characteristics of self-made nab paclitaxel compared to Abraxane were observed in morphology, encapsulation efficiency, in vitro release, X-ray diffraction analysis, differential scanning calorimetry analysis, and circular dichroism spectra analysis. Consistent concentration-time curves in rats, biodistributions in mice, anti-tumor activities in mice, and histological transmutation in mice were also found between Abraxane and self-made nanoparticles. In a word, our novel preparative method for nab paclitaxel can significantly improve drug loading, obviously decrease product cost, and is considered to have potent practical value.

Three-dimensional reconstruction of the uterine vascular supply through vascular casting and thin slice computed tomography scanning.

It was the objective of this study to construct a model of the uterine vascular supply through vascular casting and thin slice computed tomography scanning. This will provide a teaching aide for the understanding of uterine artery embolization (UAE) procedures, as well as normal uterine and ovarian arterial anatomy. Using 20% chlorinated poly vinyl chloride, we infused and cast a set of a normal uterus, vagina and bilateral adnexa through the uterine artery and ovarian artery. After thin slice CT scanning, we obtained the three-dimensional (3D) reconstruction by maximum intensity projection (MIP) and surface-shaded display (SSD), and then observed its figure and characteristics. A model of the uterine vascular supply can be successfully reconstructed by vascular casting and thin slice CT scanning. The 3D reconstruction offers a clear view of the course of the uterine artery and its blood supply distribution. It has two major branches: The intramuscular uterine branch and the cervicovaginal branch (1). Blood supply is generally unilateral, with communicating branches between the two sides and possible anastomoses between the arterial blood supply of the uterus and the ovaries. The major blood supply of the cervix comes from the cervicovaginal branch of the uterine artery, while the vaginal arterial supply derives directly from the internal iliac artery. The CT technique allows real-time 360 degrees rotation and changes in model for in-depth study of the vascular network and its adjacent tissues. It is possible to construct an in vitro uterine arterial network by vascular casting and CT scanning, which can provide unique insight into the female genitourinary system arterial network. Based on this, we can create reconstructions as well as models for different diseases such as leiomyomata, adenomyosis, and endometrial cancer. These models will provide morphological evidence to the interventional therapy and UAE teaching in Obstetrics and Gynecology.

Epidemiological analysis of respiratory and intestinal infectious diseases in three counties of Sichuan: the baseline survey of Disaster Mitigation Demonstration Area in western China.

BACKGROUND: Natural disasters can indirectly induce epidemics of infectious diseases through air and water pollution, accelerated pathogen reproduction, and population migration. This study aimed to explore the epidemiological characteristics of the main infectious diseases in Sichuan, a province with a high frequency of natural disasters. METHODS: Data were collected from the local Centers for Disease Control infectious disease reports from Lu, Shifang and Yuexi counties from 2011 to 2015 and from the baseline survey of the Disaster Mitigation Demonstration Area in Western China in 2016. Principal component regression was used to explore the main influencing factors of respiratory infectious diseases (RIDs). RESULTS: The incidence rates of RIDs and intestinal infectious diseases (IIDs) in 2015 were 78.99/100,000, 125.53/100,000, 190.32/100,000 and 51.70/100,000, 206.00/100,000, 69.16/100,000 in Lu, Shifang and Yuexi respectively. The incidence rates of pulmonary tuberculosis (TB) was the highest among RIDs in the three counties. The main IIDs in Lu and Shifang were hand-foot-mouth disease (HFMD) and other infectious diarrhea; however, the main IIDs in Yuexi was bacillary dysentery. The proportions of illiterate and ethnic minorities and per capita disposable income were the top three influencing factors of RIDs. CONCLUSIONS: TB was the key point of RIDs prevention among the three counties. The key preventable IIDs in Lu and Shifang were HFMD and other infectious diarrhea, and bacillary dysentery was the major IIDs in Yuexi. The incidence rates of RIDs was associated with the population composition, the economy and personal hygiene habits.

Preparation and Evaluation of Oxaliplatin Thermosensitive Liposomes with Rapid Release and High Stability.

Oxaliplatin (OXP) was reported to show low anti-tumor activity when used alone and to display side effects; this low activity was attributed to high partitioning to erythrocytes and low accumulation in tumors. Thermosensitive liposomes (TSL) were considered able to specifically deliver drugs to heated tumors and to resolve the OXP distribution problem. Regretfully, TSL encapsulating doxorubicin did not demonstrate significant improvement in progression-free survival. Drug release below 41°C and significant leakage were considered major reasons for the failure. The purpose of this study was to acquire OXP TSL with rapid release at the triggered temperature and high stability at body temperature and at storage temperatures. A small quantity of poloxamer 188 was introduced into the TSL formulation to stabilize the encapsulated drug. It was shown that the addition of poloxamer 188 had no influence on the TSL characteristics. More than 90% of OXP was released within 10 min at 42°C, and less than 15% was released within 60 min at temperatures below 39°C. TSL were stable at 37°C for 96 h and at 4°C for 6 months. The anti-tumor activity of TSL at the dose of 2.5 mg/kg was certified to be equal to those of OXP injection and non-thermosensitive liposomes (NTSL) at the dose of 5 mg/kg, and significant improvement of tumor inhibition was observed in TSL compared with injection and NTSL at the same dose. It was also shown from the histological transmutation of tumors that TSL had stronger anti-tumor activity. Therefore, it could be concluded that TSL composed of a proper amount of poloxamer had rapid release and high stability, and OXP TSL would be anticipated to exert prominent anti-tumor activity in the clinic.

Preparation, characterization, and efficacy of thermosensitive liposomes containing paclitaxel.

To increase the anti-tumor activity of paclitaxel (PTX), novel temperature-sensitive liposomes loading paclitaxel (PTX-TSL) were developed. In vitro, characteristics of PTX-TSL were evaluated. The mean particle diameter was about 100 nm, and the entrapment efficiency was larger than 95%. The phase-transition temperature of PTX-TSL determined by differential scanning calorimetry was about 42 °C. The result of in vitro drug release from PTX-TSL illustrated that release rate at 37 °C was obviously lower than that at 42 °C. Stability data indicated that the liposome was physically and chemically stable for at least 3 months at -20 °C. In vivo study, after three injections with hyperthermia in the xenograft lung tumor model, PTX-TSL showed distinguished tumor growth suppression, compared with non-temperature-sensitive liposome and free drug. The results of intratumoral drug concentration indicated that PTX-TSL combined with hyperthermia delivered more paxlitaxel into the tumor location than the other two paxlitaxel formulations. In summary, PTX-TSL combined with hyperthermia significantly inhibited tumor growth, due to the increased targeting efficiency of PTX to tumor tissues. Such approach may enhance the delivery efficiency of chemotherapeutics into solid tumors.

In Vitro and In Vivo Evaluations of PLGA Microspheres Containing Nalmefene.

Poor patient compliance, untoward reactions and unstable blood drug levels after the bolus administration are impeding the pharmacotherapy for insobriety. A long-acting preparation may address these limitations. The aim of this paper was to further investigate the in vitro characteristics and in vivo performances of nalmefene microspheres. Nalmefene was blended with poly (lactide-co-glycolide) (PLGA) to prepare the target microspheres by an O/O emulsification solvent evaporation method. The prepared microspheres exhibited a controlled release profile of nalmefene in vitro over 4 weeks, which was well fitted with a first-order model. In vitro degradation study showed that the drug release in vitro was dominated by both drug diffusion and polymer degradation mechanisms. Pharmacokinetics study indicated that the prepared microspheres could provide a relatively constant of nalmefene plasma concentration for at least one month in rats. The in vivo pharmacokinetics profile was well correlated with the in vitro drug release. Pharmacodynamics studies revealed that the drug loaded microspheres could produce a long-acting antagonism efficacy on rats. These results demonstrated the promising application of injectable PLGA microspheres containing nalmefene for the long-term treatment of alcohol dependence.

A novel drug-polyethylene glycol liquid compound method to prepare 10-hydroxycamptothecin loaded human serum albumin nanoparticle.

Drug loading strategies and the methods derived for implementing those strategies are crucially important to the preparation of drug loaded human serum albumin nanoparticles (HSA-NPs), because each of them is focused on wrapping up specific types of drugs via certain physical and chemical properties. However, poor adaptability still exists to load drugs like model substance 10-hydroxycamptothecin (HCPT) by conventional methods. Because it typically represents a large class of water-insoluble drugs, who also structurally possess a certain number of hydrophilic groups. So even though they majorly have lipophilicity but they are of low liposolubility. This article presents a new concept of a loading strategy that takes a drug polymer liquid compound as a loading medium. The drug polymer liquid compound was made from low weight polyethylene glycol (l-PEG) and HCPT. Consequently, this strategy has managed to fabricate HCPT-loaded HSA-NPs through an unconventional approach that overcomes drawbacks of current loading means and better results have been obtained, like high entrapment efficiency (over 99%) and less toxicity involvement. Afterward, in vitro and in vivo evaluations and characterizations were performed to help with the in-depth interpretation of the loading mechanism in order to reveal and further investigate the possible far-reaching applications of this method.