Research progress in integrated diagnosis and treatment platform based on magnetic nanoparticles / 国际生物医学工程杂志

Theranotics, an integrated diagnosis and treatment nanoplatform technology based on nanomaterials, integrates the diagnosis and treatment of diseases seamlessly and shows a broad prospect in medical practice. With the rapid development of nanomedicine, the technology of magnetic nanoparticles (MNPs) synthesis is becoming more and more mature. MNPs have controllable shape and particle size, admirable stability and biocompatibility, excellent magnetic properties, and can be readily chemically modified. These advantages make them widely used in clinical practice, such as diagnosis, targeted drug delivery, medical imaging, hyperthermia therapy, and radiotherapy, which also make MNPs high-quality materials for integrated diagnosis and treatment platforms.In this paper, the research progress of MNPs in the areas of magnetically guided drug delivery, magnetic thermotherapy, and multimodal imaging was reviewed; their advantages as an integrated platform for diagnosis and treatment were discussed; and the problems faced in research and application prospects were summarized and outlooked.

Nanodiamonds with powerful ability for drug delivery and biomedical applications: Recent updates on in vivo study and patents / 药物分析学报

Nanodiamonds are novel nanosized carbon building blocks possessing varied fascinating mechanical, chemical, optical and biological properties, making them significant active moiety carriers for biomedical application. These are known as the most'captivating' crystals attributed to their chemical inertness and unique properties posing them useful for variety of applications in biomedical era. Alongside, it becomes increasingly important to find, ascertain and circumvent the negative aspects associated with nano-diamonds. Surface modification or functionalization with biological molecules plays a significant role in managing the toxic behavior since nanodiamonds have tailorable surface chemistry. To take advantage of nanodiamond potential in drug delivery, focus has to be laid on its purity, surface chemistry and other considerations which may directly or indirectly affect drug adsorption on nanodiamond and drug release in biological environment. This review emphasizes on the basic properties, synthesis techniques, surface modification techniques, toxicity issues and biomedical applications of nanodiamonds. For the devel-opment of nanodiamonds as an effective dosage form, researchers are still engaged in the in-depth study of nanodiamonds and their effect on life interfaces.

Exosomes: An endogenous natural nano-drug delivery system / 中国药理学通报

Exosomes are naturally nanometer-sized (40-100 nm) vesicles that contribute to the communication among the cells through the proteins, lipids and RNA which they carried. Exosomes derived at different physiological conditions play different role, which therefore can be widely used in the diagnosis and treatment of cancer. Besides, exosomes as the natural nanomaterials have the unique advantage in drug delivery system. Although the intrinsic advantages of exosomes have evoked a surge of interest, improvements in standardized isolation techniques with high efficiency and robust yield are still a huge challenge. Here, we provide an overview of the isolation and the application of exosomes in drug delivery system.

Lipid core nanoparticles resembling low-density lipoprotein and regression of atherosclerotic lesions: effects of particle size

Particles are usually polydispersed and size is an important feature for lipid-based drug delivery systems in order to optimize cell-particle interactions as to pharmacologic action and toxicity. Lipid nanoparticles (LDE) with composition similar to that of low-density lipoprotein carrying paclitaxel were shown to markedly reduce atherosclerosis lesions induced in rabbits by cholesterol feeding. The aim of this study was to test whether two LDE fractions, one with small (20-60 nm) and the other with large (60-100 nm) particles, had different actions on the atherosclerotic lesions. The two LDE-paclitaxel fractions, prepared by microfluidization, were separated by density gradient ultracentrifugation and injected (4 mg/body weight, intravenously once a week) into two groups of rabbits previously fed cholesterol for 4 weeks. A group of cholesterol-fed animals injected with saline solution was used as control to assess lesion reduction with treatment. After the treatment period, the animals were euthanized for analysis. After treatment, both the small and large nanoparticle preparations of LDE-paclitaxel had equally strong anti-atherosclerosis action. Both reduced lesion extension in the aorta by roughly 50%, decreased the intima width by 75% and the macrophage presence in the intima by 50%. The two preparations also showed similar toxicity profile. In conclusion, within the 20-100 nm range, size is apparently not an important feature regarding the LDE nanoparticle system and perhaps other solid lipid-based systems.

The progress of novel drug delivery systems / 药学学报

The development of pharmaceuticals has been providing many kinds of novel drug delivery systems, which are important for improving therapeutic effect and one of the most important fields in pharmaceutics. According to their application, we can generally divide the novel drug delivery systems into three categories:quickly performed drug delivery system, long-term drug delivery system and high effective drug delivery system. Some diseases, such as asthma, angina pectoris and migraine, require therapeutics urgently, and the drugs have to be absorbed in several minutes. Therefore, quickly performed drug delivery systems are developed, such as oral disintegrating tablets and nasal spray. For normal tablets and capsules, especially the drugs with short blood half life, the drug concentration in blood shows obvious peak-valley phenomenon, which reduces the therapeutic effect and requires multiple administration. To solve this problem, sustained drug release system was developed, which could release the drugs slowly and sustainably even in zero-order kinetics. The pulse drug delivery system was developed that can delayed and pulsed release drug for one or several times. This system is especially useful in the management of asthma and heart disease, which are often found in midnight or early morning when patients are in bed. Transdermal drug delivery system could release drugs sustainably and deliver the drugs through skin to blood circulation, providing long term activity. The water-insoluble drugs are difficult for pharmaceutical development, thus many methods were developed to improve the solubility and bioavailability of drugs. Although biopharmaceuticals are important for disease treatment, the application shadows by the poor stability and low bioavailability. Thus the biopharmaceutical delivery system was developed, which mainly focused on structure modification and encapsulation by carriers. Considering therapeutic effect requires interaction between drugs and their targets, it is important to deliver drugs to their targets. Therefore, targeting delivery systems were developed, which mainly based on the nanoparticles. Furthermore, on-demand release drug delivery systems are also developed with the property of environment-triggered drug release. In conclusion, the novel drug delivery systems were reviewed in this study.

Comparison of different administration routes of saikosaponin in plasma pharmacokinetics and brain pharmacokinetics / 中国中药杂志

To evaluate the optimum administration routes of saikosaponin in the treatment of epilepsy by comparing the plasma pharmacokinetics and the brain pharmacokinetics after different administration routes of saikosaponin. After receiving saikosaponin in different administration routes, the mice were sacrificed to collect the blood and brain tissues. The acetonitrile and methanol (9∶1) were used to precipitate the plasma protein. The concentration of the SSa in mice plasma and brain was determined by UPLC-MS/MS, and the pharmacokinetic parameters, bioavailability, the brain targeting coefficient (Re) and the brain drug targeting index (DTI) were calculated with Kinetica software. The relative brain Re was 142.17% by intranasal administration, with DTI of 3.06, significantly higher than those by the injections; in addition, the brain DTI was 1.25 by gavage administration. The brain drug targeting of saikosaponin by intranasal administration was higher than that by injection and gavage administration, indicating the advantages of the intranasal administration on medicine absorption into the brain.

Treatment of patients with aortic atherosclerotic disease with paclitaxel-associated lipid nanoparticles

OBJECTIVE: The toxicity of anti-cancer chemotherapeutic agents can be reduced by associating these compounds, such as the anti-proliferative agent paclitaxel, with a cholesterol-rich nanoemulsion (LDE) that mimics the lipid composition of low-density lipoprotein (LDL). When injected into circulation, the LDE concentrates the carried drugs in neoplastic tissues and atherosclerotic lesions. In rabbits, atherosclerotic lesion size was reduced by 65% following LDE-paclitaxel treatment. The current study aimed to test the effectiveness of LDE-paclitaxel on inpatients with aortic atherosclerosis. METHODS: This study tested a 175 mg/m2 body surface area dose of LDE-paclitaxel (intravenous administration, 3/3 weeks for 6 cycles) in patients with aortic atherosclerosis who were aged between 69 and 86 yrs. A control group of 9 untreated patients with aortic atherosclerosis (72-83 yrs) was also observed. RESULTS: The LDE-paclitaxel treatment elicited no important clinical or laboratory toxicities. Images were acquired via multiple detector computer tomography angiography (64-slice scanner) before treatment and at 1-2 months after treatment. The images showed that the mean plaque volume in the aortic artery wall was reduced in 4 of the 8 patients, while in 3 patients it remained unchanged and in one patient it increased. In the control group, images were acquired twice with an interval of 6-8 months. None of the patients in this group exhibited a reduction in plaque volume; in contrast, the plaque volume increased in three patients and remained stable in four patients. During the study period, one death unrelated to the treatment occurred in the LDE-paclitaxel group and one death occurred in the control group. CONCLUSION: Treatment with LDE-paclitaxel was tolerated by patients with cardiovascular disease and showed the potential to reduce atherosclerotic lesion size.

La nanotecnología aplicada al desarrollo de medicamentos / Nanotechnology applied to drug development

En este trabajo se realiza una revisión de las principales estrategias definidas hasta la fecha para el desarrollo de sistemas nanoparticulares farmacéuticos y de su interés en terapéutica, Se trata de liposomas, nanopartículas poliméricas o lipídicas, micelas poliméricas, dendrímeros, conjugados poliméricos y con anticuerpos, nanotubos de carbono y otros nanotransportadores, que tras su administración posibilitan la vectorización o localización selectiva de la sustancia que transportan a nivel de un órgano, de un tejido, de un tipo específico de células o incluso a nivel de orgánulos celulares concretos. En la actualidad, las principales dianas en vectorización son las células tumorales y la neovascularización tumoral, las células del sistema fagocítico mononuclear y las células somáticas dañadas. La vectorización a estas dianas se puede alcanzar mediante un mecanismo pasivo, un mecanismo mediado por un desencadenante externo 0 un mecanismo activo.

This paper reviews the main strategies defined to date for the development of pharmaceutical nanoparticle systems and their interest in therapy. These are Iiposomes, polymeric or lipid nanoparticles, polymeric micelles, dendrimers, polymer conjugates and antibodies, carbon nanotubes and other nanocarriers, which upon administration enable targeting or selective localization of substance transporting at level of an organ, a tissue, a specific cell type or even at specific cellular organelles. Currently, the main targets in drug targeting are tumor cells and tumor neovascularization, the mononuclear phagocyte system cells and somatic cells damaged. Drug localization to these targets can be achieved by a passive mechanism, a mechanism mediated by an external trigger or an active mechanism.

Comparative study on survival of patients with metastatic colorectal cancer treated with different molecular targeted drug delivery / 中国生化药物杂志

Objective To study bevacizumab combined with chemotherapy regimen in treatment of different metastasis survival in patients with colorectal cancer, in order to optimize the scheme selection of bevacizumab for metastatic colorectal cancer metastasis , improve survival and quality of life of patients with rectal cancer.Methods 128 cases of late January 2013~2013 year in June in general hospital of medical university for treatment of metastatic colorectal cancer patients as the research object, which were randomLy divided into A, B, C, D 4 groups, 32 cases in each group, respectively with bevacizumab (5 mg/kg) combined with FOLFIRI and bevacizumab (10 mg/kg) combined with FOLFIRI and bevacizumab (5 mg/kg) combined with FOLFOX and bevacizumab ( 10 mg/kg ) therapy combined with FOLFIRI regimen, four patients underwent 6 cycles of treatment.Comparison of four groups of patients with recent clinical efficacy, progression free survival (survival progression-free, PFS), three years survival rate, overall survival (overall survival, OS).Results Four groups of patients with gender, age, stage of disease, ECOG score before treatment, primary tumor site, tumor metastasis, metastasis tumor diameter, there were no significant differences.Toxicity of different degrees occurred in the four groups during treatment, but the patients tolerated and complete the established chemotherapy.A, B, C, D group total effective rate were 56.25%, 59.38%, 46.88%, 50%, 3 years survival rates were 25%, 18.75%, 28.13%, 18.75%, PFS respectively: (9.5 ±1.1), (9.6 ±1.1), (9.2 ±1), (9.3 ± 0.9) months, overall survival were: (30.23 ±2.26), (29.83 ±2.24), (26.94 ±2.08), (27.19 ±2.11) months.A, B group of patients in the clinical total effective rate, three years survival rate were higher than that of C and D two groups, but there were no statistically significant difference between the two groups.A, DFS and TTP in B group were significantly higher than that of C and D two groups, and there were significant differences among the groups (P all <0.05), the difference between the two groups was no statistically significant, C, D between the two groups there was no significant difference, A, B groups were significantly higher than that of C, OS in D two group, and the difference between the two groups were statistically the significance (P<0.05), A, B between the two groups, but no significant difference, C, D between the two groups there was no significant difference.Conclusion according to the 5-10 mg/kg/m2 of bevacizumab combined with FOLFIRI regimen in the treatment of metastatic colorectal cancer, can effectively improve progression free survival in patients with a high clinical value to promote the transfer of clinical overall survival of patients with colorectal cancer.

The relationship between DC-CIK and colorectal cancer prognoses and its influen-cing factors / 药学实践杂志

Objective To discuss dendritic cell-cytokine-induced killer (DC-CIK ) cell therapy effects and clinical out-comes in patients with colorectal cancer in order to have better clinical treatment .Methods A retrospective analysis of the data of 66 patients with colorectal cancer from the Biological Therapy Department of the Eastern Hepatobiliary Surgery Hospital was performed from January 2012 to January 2014 ,and then was followed up .Taking gender ,age ,degree of pathological differen-tiation ,TNM staging ,surgical methods ,and targeted therapy as the research basis ,by the Kaplan-Meier single factor and Cox multiple factors analysis we mainly discuss the DC-CIK cell treatment′s effect on the prognoses of patients .Results Kaplan-Meier single factor analysis results indicate :to a certain extent ,DC-CIK cell therapy can improve the prognoses of patients ;Cox multi-factor analysis results indicate whether accepting DC-CIK cell therapy is an independent factor influencing the prog-noses of patients .Conclusion DC-CIK cells therapy can improve the prognoses of patients with colorectal cancer .

Inducible Mouse Models for Cancer Drug Target Validation

Genetically-engineered mouse (GEM) models have provided significant contributions to our understanding of cancer biology and developing anticancer therapeutic strategies. The development of GEM models that faithfully recapitulate histopathological and clinical features of human cancers is one of the most pressing needs to successfully conquer cancer. In particular, doxycycline-inducible transgenic mouse models allow us to regulate (induce or suppress) the expression of a specific gene of interest within a specific tissue in a temporal manner. Leveraging this mouse model system, we can determine whether the transgene expression is required for tumor maintenance, thereby validating the transgene product as a target for anticancer drug development (target validation study). In addition, there is always a risk of tumor recurrence with cancer therapy. By analyzing recurrent tumors derived from fully regressed tumors after turning off transgene expression in tumor-bearing mice, we can gain an insight into the molecular basis of how tumor cells escape from their dependence on the transgene (tumor recurrence study). Results from such studies will ultimately allow us to predict therapeutic responses in clinical settings and develop new therapeutic strategies against recurrent tumors. The aim of this review is to highlight the significance of doxycycline-inducible transgenic mouse models in studying target validation and tumor recurrence.

A network pharmacology study of Sendeng-4, a Mongolian medicine / 中国天然药物

We collected the data on the Sendeng-4 chemical composition corresponding targets through the literature and from DrugBank, SuperTarget, TTD (Therapeutic Targets Database) and other databases and the relevant signaling pathways from the KEGG (Kyoto Encyclopedia of Genes and Genomes) database and established models of the chemical composition-target network and chemical composition-target-disease network using Cytoscape software, the analysis indicated that the chemical composition had at least nine different types of targets that acted together to exert effects on the diseases, suggesting a "multi-component, multi-target" feature of the traditional Mongolian medicine. We also employed the rat model of rheumatoid arthritis induced by Collgen Type II to validate the key targets of the chemical components of Sendeng-4, and three of the key targets were validated through laboratory experiments, further confirming the anti-inflammatory effects of Sendeng-4. In all, this study predicted the active ingredients and targets of Sendeng-4, and explored its mechanism of action, which provided new strategies and methods for further research and development of Sendeng-4 and other traditional Mongolian medicines as well.

Preparation of iRGD modified liposome and its targeting to colon cancer cell / 中国生化药物杂志

Objective To prepare iRGD modified liposome(iRGD-LP)and evaluate their targeting efficiency in vitro and in vivo to colon cancer cell.Methods The iRGD-LP was prepared by film-ultrasonic method,its particle size and Zeta potential were evaluated.The cellular uptake efficiency of RKO cell to LP and iRGD-LP were evaluated in vitro and in vivo.Tumor spheroid model were constructed and the penetration efficiency of solid tumor were evaluated.Ectopic colon cancer nude mice model was constructed,and iRGD -LP distribution in the rat body were studied.Results The particle diameter of iRGD-LP was (109.4 ±12.9)nm with the Zeta potential of (4.2 ±1.47)mV.The cellular uptake efficiency of RKO cell to iRGD-LP were 3.2 times higher than that of LP(P<0.01).The tumor spheroid penetration test and iRGD-LP distribution in vivo imaging results showed iRGD-LP had the strongest fluorescence intensity.Conclusion The iRGD-LP might serve as a promising colon cancer delivery system of antitumor drugs.

Study on osteosarcoma targeting of solid lipid nanoparticles modified with peptides specifically binding to human osteosarcoma cells / 中国生化药物杂志

Objective To prepare SLT peptide modified solid lipid nanoparticles(SLT-SLNs),study on its affinity to MG63 cell and tumor targeting.Methods Cellular uptake test was used to evaluate the uptake efficiency of MG63 cell for SLT-SLNs.MG63 cell were xenografted into athymic nude mice to establish the animal model,vivo imaging was used to evaluate the targeting efficiency. Results The average particle size of SLT-SLNs was (115.7 ±8.7)nm,polydispersity coefficient was 0.12,and Zeta potential was(13 ±2.25)mV.Cellular uptake test results showed that uptaken efficiency of SLT modified SLNs by MG63 cell were 4.4 times higher than that of SLNs.The fluorescence intensity of SLT-SLNs was much stronger than that of SLNs in vivo.Conclusion The SLT peptide modified solid lipid nanoparticles has a good osteosarcoma targeting efficiency,and it might serve as a promising osteosarcoma delivery system of antitumor drugs.

Preparation of transferrin and RGD co-modified PLGA nanoparticles and its targeting to melanoma / 中国生化药物杂志

Objective To prepare transferrin and Arg-Gly-Asp polypeptide co-modified nanoparticles(TF/RGD-NPs)and evaluate its targeting efficiency to melanoma.Methods The co-modified nanoparticles were prepared by emulsion method and its appearance,particle size and Zeta potential were evaluated.The cellular uptake experiment and melanoma tumor spheroids penetration test were used to evaluate the affinity and ability to penetrate tumor tissues of TF/RGD-NPs to melanoma B16 cells. Results The particle diameter of co-modified nanoparticles was(113.4 ±12.5)nm and the Zeta potential was(4.53 ±2.15)mV.In vitro uptake test demonstrated that the efficacy of cellular uptaken TF/RGD-NPs by B16 cells were 2.7 times and 2.9 times to TF-NPs and RGD-NPs,respectively,the differences were all significant(P<0.05 ).Tumor spheroid penetration test results showed that TF/RGD-NPs has good affinity to melanoma cells.Conclusion TF/RGD-NPs can target to melanoma B16 cell efficiency in vitro,it may be serve as a potential drug delivery system for targeting melanoma.

Construction of RGD-TAT modified liposomes and evaluation of its targeting on glioma / 中国生化药物杂志

Objective To construct RGD-TAT modified liposomes(RGD-TAT-LPs)and evaluate its glioma targeting efficiency.Methods RGD-TAT-LPs was constructed by film-ultrasonic method,its appearance,particle size and Zeta potential were mearsured. Cellular uptake of LPs,TAT-LPs, RGD-LPs and RGD-TAT-LPs was used to evaluate the affinity to C6 cells.C6 cells were xenografted in athymic mice to establish the animal model,which were used to evaluate the distribution of liposomes in vivo. Results The particle diameter of RGD-TAT-LPs was (1 16.5 ±1 1.3 )nm,and its Zeta potential was (23.2 ±3.5 )mV. Cellular uptake experiments demonstrated the cell uptake efficiency of RGD-TAT-LPs by C6 cells were 2.9-fold,2.3-fold and 4.7-fold than that of RGD-LPs,TAT-LPs and LPs respectively. The in vivo imaging showed that RGD-TAT-LPs had the strongest fluorescence intensity in brain. Conclusion The RGD-TAT-LPs might serve as a promising delivery system of antitumor drugs.

Antibiotic drugs targeting bacterial RNAs

RNAs have diverse structures that include bulges and internal loops able to form tertiary contacts or serve as ligand binding sites. The recent increase in structural and functional information related to RNAs has put them in the limelight as a drug target for small molecule therapy. In addition, the recognition of the marked difference between prokaryotic and eukaryotic rRNA has led to the development of antibiotics that specifically target bacterial rRNA, reduce protein translation and thereby inhibit bacterial growth. To facilitate the development of new antibiotics targeting RNA, we here review the literature concerning such antibiotics, mRNA, riboswitch and tRNA and the key methodologies used for their screening.

Efeito da combinação de sinvastatina com paclitaxel veiculado por nanoemulsão lipídica na aterosclerose induzida em coelhos / Effect of a combination of simvastatin and paclitaxel carried by a lipid nanoemulsion on induced atherosclerosis in rabbits

Em estudos prévios, mostramos que uma nanoemulsão lipídica (LDE) é reconhecida e se liga aos receptores de LDL após sua injeção na corrente sanguínea. Como tais receptores estão superexpressos em células com altas taxas de proliferação, como ocorre no câncer e na aterosclerose, a LDE pode ser utilizada como veículo para direcionar fármacos a essas células, diminuindo sua toxicidade e aumentando sua eficácia terapêutica. Anteriormente, reportamos que o tratamento com um derivado do paclitaxel, o oleato de paclitaxel, associado à LDE (PTX-LDE), reduziu em 60% a área lesionada de aortas de coelhos submetidos à dieta aterogênica, comparados a animais não tratados. No presente trabalho, avaliamos o efeito da associação de sinvastatina, medicamento hipolipemiante, e PTX-LDE, sobre a aterosclerose induzida por dieta em coelhos. Trinta e seis coelhos machos da raça Nova Zelândia foram submetidos à dieta enriquecida com 1% de colesterol durante oito semanas. A partir da quinta semana, os animais foram divididos em quatro grupos, de acordo com o tratamento: controle (solução salina EV), sinvastatina (2mg/kg/dia, VO), paclitaxel (PTX-LDE, 4mg/Kg/semana, EV), ou combinação de sinvastatina (2mg/Kg/dia, VO) com paclitaxel (PTX-LDE, 4mg/Kg/semana, EV). Após oito semanas, os animais foram sacrificados para análise das aortas. Em comparação aos controles, a área lesionada das aortas foi em torno de 60% menor, tanto no grupo paclitaxel, quanto no grupo da combinação, e em torno de 40% menor no grupo sinvastatina (p<0,05). A razão entre as camadas íntima/média foi menor nos grupos tratados, em relação ao grupo controle (controles, 0,35±0,22, sinvastatina, 0,10±0,07, paclitaxel, 0,06±0,16 e combinação, 0,09±0,05, p<0,0001). Os grupos combinação e sinvastatina apresentaram um aumento da porcentagem de colágeno nas lesões (combinação, 20% e sinvastatina, 22%), em comparação aos controles (11%) e ao grupo paclitaxel (12%), (p<0,0001). Houve uma diminuição da porcentagem de macrófagos na lesão em todos os grupos tratados (paclitaxel, 11%, sinvastatina, 8% e combinação, 5%), comparados ao grupo controle (30%), (p<0,0001). O grupo paclitaxel apresentou menor porcentagem de células musculares lisas na lesão (20%) em relação aos controles (33%), (p<0,0001), já na combinação, houve aumento dessa porcentagem (44%), (p<0,0001). A combinação com sinvastatina não aumentou a eficácia do tratamento com PTX-LDE na redução da área de lesões ateroscleróticas, porém, os efeitos adicionais sobre o perfil lipídico e na composição das lesões, observadas com o uso da combinação, são achados importantes, que sugerem benefícios no sentido de aumentar a estabilidade das placas ateroscleróticas, o que nos abre um caminho de pesquisa muito promissor

In previous studies we have shown that a lipid nanoemulsion (LDE) is recognized and binds to LDL receptors after injection into the bloodstream. As those receptors are upregulated in cells with higher proliferation rates, as occurs in cancer and atherosclerosis, LDE can be used as a vehicle to direct drugs to those cells, diminishing toxicity and increasing therapeutic efficacy. Previously, we reported that treatment with antiproliferative agent paclitaxel derivative, paclitaxel oleate, associated with LDE (PTX-LDE), reduced by 60% the injured area of the aorta of rabbits subjected to atherogenic diet compared to untreated animals. In the current study we aim to test the effect of a combination of lipid-lowering drug simvastatin with PTX-LDE on diet-induced atherosclerosis in rabbits. Thirty-six male New Zealand rabbits were fed a 1% cholesterol diet for 8 weeks. Starting from week 5, animals were divided into four groups, according to the following treatments: controls (I.V. saline solution injections), simvastatin P.O. (2mg/kg/day), paclitaxel (PTX-LDE I.V. injections, 4mg/Kg/week), or paclitaxel-simvastatin combination (PTX-LDE I.V., 4mg/Kg/week + simvastatin P.O., 2mg/Kg/day). After 8 weeks, the animals were sacrificed for aorta evaluation. Compared to controls, the injured area was reduced by 60% in both paclitaxel and combination groups, and by 40% in simvastatin group (p<0,05). The intima/media ratio was reduced in treated groups, compared to control group (controls, 0,35±0,22, simvastatin, 0,10±0,07, paclitaxel, 0,06±0,16 and combination, 0,09±0,05, p<0,0001). Simvastatin and combination groups showed increased collagen content within the lesions (simvastatin, 22% and combination 20%), compared to controls (11%) and to paclitaxel group (12%), (p <0.0001). Macrophage content within the lesions was reduced in all treated groups (paclitaxel, 11%, simvastatin, 8% e combination, 5%), compared to controls (30%), (p <0.0001). The percentage of smooth muscle cells in the lesions was diminished in paclitaxel group (20%) compared to control group (33%), while the combination group showed increased percentage (44%) of smooth muscle cells in the lesions (p<0,0001). The combination of simvastatin did not improve the efficacy of the treatment with PTXLDE in reducing the area of atherosclerotic lesions, but the additional effects on lipid profile and lesion composition observed with the use of the combination are important findings that suggest benefits in order to enhance the stability of atherosclerotic plaques, which may lead us to a very promising research path

Uso combinado de sinvastatina e paclitaxel associado à nanoemulsão lipídica no tratamento do câncer / Combined use of simvastatin and paclitaxel associated to a lipidic nanoemulsion in cancer treatment

Uma nova alternativa para o tratamento do câncer foi proposta em estudos anteriores, consistindo no uso de uma nanoemulsão lipídica como transportadora de agentes quimioterápicos às células neoplásicas. A redução da toxicidade da quimioterapia promovida pelo direcionamento específico de quimioterápicos às células tumorais nos levou a testar o potencial de aplicação do sistema de nanopartículas lipídicas na terapêutica combinada do paclitaxel com a sinvastatina, um agente hipolipemiante que pode ser empregado como coadjuvante no tratamento do câncer. Nos dias 11, 14 e 19 após a inoculação de células de melanoma B16F10, camundongos C57BL/6J receberam pela via intraperitoneal soluções de oleato de paclitaxel associado à nanoemulsão lipídica 17,5µmol/kg (Nano-paclitaxel), formulação comercial do paclitaxel 17,5µmol/kg, nanoemulsão lipídica (Nanoemulsão) e solução salina (Controle). A sinvastatina 50mg/kg/dia foi administrada por gavagem do 11° ao 19° dia após a inoculação do tumor em um dos grupos de animais tratados com o Nano-paclitaxel (Nano-paclitaxel + Sinva), no grupo tratado com a formulação comercial do paclitaxel (Paclitaxel + Sinva) e como monoterapia (Sinva). Camundongos Balb-c saudáveis receberam os mesmos tratamentos para avaliação dos possíveis efeitos tóxicos dos diferentes tratamentos. A terapia combinada Nano-paclitaxel + Sinva apresentou toxicidade negligível em comparação com a terapia combinada Paclitaxel + Sinva que provocou perda de peso e mielossupressão nos animais. Nos animais portadores de tumor, o tratamento Nano-paclitaxel + Sinva inibiu 95% do crescimento tumoral, comparado à inibição de 44% promovida pelo tratamento Paclitaxel + Sinva. Além disso, apenas 37% dos animais portadores de melanoma submetidos ao tratamento com Nano-paclitaxel + Sinva apresentaram metástases, em contraste com 90% dos tratados com Paclitaxel + Sinva. A probabilidade de sobrevida também foi maior nos camundongos tratados com o Nano-paclitaxel + Sinva em comparação aos tratados com Paclitaxel + Sinva. A análise de amostras de tumores por citometria de fluxo mostrou que somente nos grupos de animais tratados com Sinva, Nano-paclitaxel ou com a combinação Nano-paclitaxel + Sinva houve aumento na expressão de p21 em comparação ao grupo Controle. Da mesma forma, apenas nos grupos Sinva e Nano-paclitaxel + Sinva houve redução na expressão de ciclina D1 em comparação ao grupo Controle. O teste de viabilidade celular com rodamina 123 mostrou despolarização da membrana mitocondrial com redução no número de células tumorais viáveis em todos os grupos de tratamentos em comparação aos grupos Nanoemulsão e Controle. A avaliação histológica dos tumores demonstrou que os grupos Nanoemulsão e Controle apresentaram alta densidade de células tumorais, diferentemente dos demais grupos de tratamento e que apenas os tumores do grupo Nano-paclitaxel + Sinva apresentaram aumento na presença de fibras de colágeno tipo I e III. Em comparação ao grupo Controle, os tumores dos grupos Sinva, Paclitaxel + Sinva, Nano-paclitaxel e Nano-paclitaxel + Sinva apresentaram redução na expressão imunohistoquímica de ICAM, MCP-1 e MMP-9 sendo que o grupo Nano-paclitaxel + Sinva apresentou a menor porcentagem de área marcada positivamente para a MMP-9. A terapia combinada com Nano-paclitaxel + Sinva é menos tóxica e mais efetiva na inibição do crescimento tumoral do que a mesma terapia com a formulação comercial do paclitaxel

In previous studies we have proposed a novel approach for cancer treatment consisting of the use of a lipid nanoemulsion as a vehicle to direct chemotherapeutic agents to neoplastic cells. Reduction of chemotherapy toxicity promoted by specific targeting of antineoplastic agents to tumor cells led us to test the application of the lipidic nanoparticle system in combined treatment with paclitaxel and simvastatin, a cholesterol-lowering drug that can be used as coadjuvant in cancer treatment. On days 11, 14 and 19 after B16F10 melanoma cells inoculation, C57BL/6J mice were intraperitoneally injected with paclitaxel oleate associated to the lipidic nanoemulsion 17.5 µmol/kg (Nano-paclitaxel), commercial formulation of paclitaxel 17.5 µmol/kg, lipidic nanoemulsion (Nanoemulsion) or saline solution (Control). Simvastatin 50 mg/kg/day was administered by gavage from days 11 to 19 after tumor inoculation in one group of animals treated with Nano-paclitaxel (Nano-paclitaxel + Simva), in the group treated with commercial formulation of paclitaxel (Paclitaxel + Simva) and as monotherapy (Simva). Evaluation of possible toxic effects of the treatments was accessed in healthy Balb-c mice. Combined therapy with Nano-paclitaxel + Simva showed negligible toxicity as compared with the combination of Paclitaxel + Simva which resulted in animal weight loss and myelosuppression. In tumor-bearing animals, treatment with Nano-paclitaxel + Simva resulted in a remarkable tumor growth inhibition rate of 95%, compared to a 44% inhibition rate promoted by treatment with Paclitaxel + Simva. Moreover, only 37% of melanoma bearing animals treated with Nano-paclitaxel + Simva developed metastasis, in contrast to 90% of those treated with Paclitaxel + Simva. Survival rates were also higher in mice treated with Nano-paclitaxel + Simva in comparison to Paclitaxel + Simva treated animals. Analysis of tumor samples by flow cytometry showed that only animals treated with Simva, Nano-paclitaxel or Nano-paclitaxel + Simva increased the expression of p21 in comparison to Control group. Also, tumors from animals treated with Simva or Nano-paclitaxel + Simva presented a decrease in the expression of cyclin D1 in comparison to Control group. Cell viability test with rhodamine 123 showed mitochondrial membrane depolarization with reduction of tumor viable cells in all treatment groups in comparison to Nanoemulsion and Control groups. The histological study revealed that in contrast to drugs treated groups, tumors from Nanoemulsion and Control groups presented high tumor cell density and only Nano-paclitaxel + Simva treated animals presented tumors with increased presence of collagen fibers I and III. In comparison to Control group, tumors from groups Simva, Paclitaxel + Simva, Nano-paclitaxel and Nano-paclitaxel + Simva showed a reduction in immunohistochemical expression of ICAM, MCP-1 and MMP-9 and the group Nano-paclitaxel + Simva presented the lowest percentage of area positively stained for MMP-9. Combined therapy with Nano-paclitaxel + Simva was less toxic and more effective in promoting tumor growth inhibiton than the same combined therapy with the commercial formulation of paclitaxel

Anti-AIDS drugs targeting drug delivery systems: Research advances / 国际药学研究杂志

The discovery and utilization of anti-AIDS drugs therapy have not only increased lifespan, but also enhanced the quality of life of HIV infected people. However, limitations of currently available drug regimens and dosage forms often fail to effectively reduce the HIV viral load in the viral reservoirs in vivo. To overcome the drawbacks of present anti-AIDS drugs' dosage forms, engineered nanocarriers including polymeric nanoparticles, liposomes, solid lipid nanoparticles and dendrimers are developed to facilitate these drugs targeting to the HIV viral reservoirs. This article reviews recent advances in the field of targeting drug delivery systems for the treatment of AIDS.