Pure drug nano-assemblies: A facile carrier-free nanoplatform for efficient cancer therapy

Nanoparticulate drug delivery systems (Nano-DDSs) have emerged as possible solution to the obstacles of anticancer drug delivery. However, the clinical outcomes and translation are restricted by several drawbacks, such as low drug loading, premature drug leakage and carrier-related toxicity. Recently, pure drug nano-assemblies (PDNAs), fabricated by the self-assembly or co-assembly of pure drug molecules, have attracted considerable attention. Their facile and reproducible preparation technique helps to remove the bottleneck of nanomedicines including quality control, scale-up production and clinical translation. Acting as both carriers and cargos, the carrier-free PDNAs have an ultra-high or even 100% drug loading. In addition, combination therapies based on PDNAs could possibly address the most intractable problems in cancer treatment, such as tumor metastasis and drug resistance. In the present review, the latest development of PDNAs for cancer treatment is overviewed. First, PDNAs are classified according to the composition of drug molecules, and the assembly mechanisms are discussed. Furthermore, the co-delivery of PDNAs for combination therapies is summarized, with special focus on the improvement of therapeutic outcomes. Finally, future prospects and challenges of PDNAs for efficient cancer therapy are spotlighted.

Atovaquone, chloroquine, primaquine, quinine and tetracycline: antiproliferative effects of relevant antimalarials on Neospora caninum / Atovaquona, cloroquina, primaquina, quinino e tetraciclina: efeitos antiproliferativos de antimaláricos relevantes em Neospora caninum

Abstract Neospora caninum is an apicomplexan parasite that causes abortion in cattle, resulting in significant economic losses. There is no commercial treatment for neosporosis, and drug repositioning is a fast strategy to test possible candidates against N. caninum. In this article, we describe the effects of atovaquone, chloroquine, quinine, primaquine and tetracycline on N. caninum proliferation. The IC50 concentrations in N. caninum were compared to the current information based on previous studies for Plasmodium and Toxoplasma gondii, correlating to the described mechanisms of action of each tested drug. The inhibitory patterns indicate similarities and differences among N. caninum, Plasmodium and T. gondii. For example, atovaquone demonstrates high antiparasitic activity in all the analyzed models, while chloroquine does not inhibit N. caninum. On the other hand, tetracycline is effective against Plasmodium and N. caninum, despite its low activity in T. gondii models. The repurposing of antimalarial drugs in N. caninum is a fast and inexpensive way to develop novel formulations using well-established compounds.

Resumo Neospora caninum é um parasita Apicomplexa relacionado a abortos no gado bovino, que resultam em impactos econômicos. Não há tratamento comercial para neosporosis e o reposicionamento de drogas indica uma estratégia rápida para testar candidatos anti-N. caninum. Neste artigo, são descritos os efeitos da atovaquona, cloroquina, quinino, primaquine e tetraciclina na proliferação de N. caninum. As concentrações IC50 em N. caninum foram comparadas com a informação disponível, baseada em estudos publicados previamente para Plasmodium e Toxoplasma gondii, incluindo a correlação com os mecanismos de ação descritos para cada droga testada. Os padrões de inibição indicam pontos de similaridades e diferenças entre N. caninum, Plasmodium e T. gondii. Por exemplo, a atovaquona demonstra uma alta atividade antiparasitária em todos os modelos testados, enquanto a cloroquina não inibe N. caninum. Por outro lado, a tetraciclina é efetiva contra Plasmodium e N. caninum, em contraste com a baixa atividade em modelos de T. gondii. O reposicionamento de drogas antimaláricas em N. caninum é uma forma rápida e de baixo custo para o desenvolvimento de novas formulações que usam compostos bem estabelecidos.

Preparation and enhanced photodynamic therapy of supramolecular nanoparticles to overcome tumor hypoxia / 药学学报

The therapeutic effect of tumor photodynamic therapy is severely limited by the hypoxic tumor microenvironment. Inhibiting tumor celloxygen consumption is a more effective way than increasing its oxygen supply to overcome the tumor hypoxia and enhance photodynamic therapy. To carry out this strategy, the supramolecular nanoparticles VER-ATO-SMN loaded with photosensitizer verteporfin (VER), oxygen-consuming inhibitor atovaquone (ATO), and stabilizer polyvinylpyrrolidone (PVP)-K30 were prepared by the nanoprecipitation method, and the optimal prescription was screened and optimized by single factor experiments. The results showed that the optimal prescription for VER-ATO-SMN was ATO∶VER (w/w) = 1∶1, PVP-K30 = 100 mg, N,N-dimethylformamide∶water (v/v) = 1∶10. The morphology, particle size, particle dispersion index and encapsulation efficiency of supramolecular nanoparticles were characterized. The VER-ATO-SMN showed a spherical morphology and was well dispersed. The hydrodynamic size of VER-ATO-SMN was 101.21 ± 4.30 nm as determined by dynamic light scattering (DLS). The encapsulation efficiencies of VER and ATO in VER-ATO-SMN prepared with the optimal prescription were 70.86% and 77.52%, respectively. The VER-ATO-SMN exhibited good laser stability and also showed high stability in conditions which simulated the physiological solution. Compared with free VER and VER liposome, VER-ATO-SMN performed enhanced therapeutic effect at the cell level. The mechanism was that VER-ATO-SMN could effectively incorporate into cells and improving the intracellular oxygen concentration by reducing the oxygen consumption of tumor cells could increase the amount of reactive oxygen species generated by VER mediated photodynamic therapy. The in vivo anticancer efficacy results of tumor-bearing mice suggested that VER-ATO-SMN could effectively inhibit the tumor growth or even completely eliminate the tumor. All animal experiments were performed in line with national regulations and approved by the Animal Experiments Ethical Committee of 900 Hospital of the Joint Logistics Team.

Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1, 4-naphthoquinones through molecular modelling

BACKGROUND Malaria persists as a major public health problem. Atovaquone is a drug that inhibits the respiratory chain of Plasmodium falciparum, but with serious limitations like known resistance, low bioavailability and high plasma protein binding. OBJECTIVES The aim of this work was to perform molecular modelling studies of 2-hydroxy-1,4-naphthoquinones analogues of atovaquone on the Qo site of P. falciparum cytochrome bc1 complex (Pfbc1) to suggest structural modifications that could improve their antimalarial activity. METHODS We have built the homology model of the cytochrome b (CYB) and Rieske iron-sulfur protein (ISP) subunits from Pfbc1 and performed the molecular docking of 41 2-hydroxy-1,4-naphthoquinones with known in vitro antimalarial activity and predicted to act on this target. FINDINGS Results suggest that large hydrophobic R2 substituents may be important for filling the deep hydrophobic Qo site pocket. Moreover, our analysis indicates that the H-donor 2-hydroxyl group may not be crucial for efficient binding and inhibition of Pfbc1 by these atovaquone analogues. The C1 carbonyl group (H-acceptor) is more frequently involved in the important hydrogen bonding interaction with His152 of the Rieske ISP subunit. MAIN CONCLUSIONS Additional interactions involving residues such as Ile258 and residues required for efficient catalysis (e.g., Glu261) could be explored in drug design to avoid development of drug resistance by the parasite.

Compliance with Atovaquone-Proguanil against Malaria of Korean Travelers Abroad

BACKGROUND: Recently, many Korean people travel abroad where malaria is prevalent. However, in Korea, relatively little is known about compliance of chemoprophylaxis against malaria. This study was performed to determine the factors influencing compliance of chemoprophylaxis against malaria in Korean travelers. MATERIALS AND METHODS: Face to face interview, telephone interview and e-mail correspondence were performed to 241 people who were prescribed with atovaquone-proguanil at the international travelers' clinic of National Medical Center between February 2007 and October 2007. RESULTS: Total of 55 people out of 235 reported one or more events of adverse reactions after chemoprophylaxis (total 76 events). However, in 38 adverse events the link between chemoprophylaxis and adverse events were very weak. Compliance of malaria chemoprophylaxis with atovaquone-proguanil was 53.9% in the study group. The predictive factors for non-compliance were package tour, travel of business affair and young age group. Conclusions: Compliance of malaria chemoprophylaxis in Korea travelers was low compared with Dutch and French studies. More efforts to increase compliance are needed, especially in travelers on package tour, business travel and people under age 40.

Compliance with Atovaquone-Proguanil against Malaria of Korean Travelers Abroad

BACKGROUND: Recently, many Korean people travel abroad where malaria is prevalent. However, in Korea, relatively little is known about compliance of chemoprophylaxis against malaria. This study was performed to determine the factors influencing compliance of chemoprophylaxis against malaria in Korean travelers. MATERIALS AND METHODS: Face to face interview, telephone interview and e-mail correspondence were performed to 241 people who were prescribed with atovaquone-proguanil at the international travelers' clinic of National Medical Center between February 2007 and October 2007. RESULTS: Total of 55 people out of 235 reported one or more events of adverse reactions after chemoprophylaxis (total 76 events). However, in 38 adverse events the link between chemoprophylaxis and adverse events were very weak. Compliance of malaria chemoprophylaxis with atovaquone-proguanil was 53.9% in the study group. The predictive factors for non-compliance were package tour, travel of business affair and young age group. Conclusions: Compliance of malaria chemoprophylaxis in Korea travelers was low compared with Dutch and French studies. More efforts to increase compliance are needed, especially in travelers on package tour, business travel and people under age 40.

A Case of Human Babesiosis Confirmed by Polymerase Chain Reaction and Treated with Atovaquone and Azithromycin

Human babesiosis is a tick-borne infectious disease caused by Babesia species. The clinical diagnosis is difficult because of nonspecific symptoms like flu. Rapid diagnosis of human babesiosis is microscopic examination in peripheral blood smear (Giemsa-stain) which reveals characteristic forms of an intracellular quadruplet parasite. But differentiation between Babesia microti and Plasmodium species can be quite difficult because of the morphologic similarity. We experienced a case of human babesiosis. The patient was a 62-year old Korean male who had been in New Jersey, U.S.A for 2 months. We initially diagnosed as malaria infection because the peripheral blood smear revealed intracellular single ring form organism. But the patient was not improved significantly by the treatment with chloroquine regimen. Finally we confirmed human babesiosis by polymerase chain reaction for Babesia microti. We treated the patient successfully with a regimen of atovaquone and azithromycin which has fewer adverse reactions than a regimen of clindamycin and quinine.

A Case of Human Babesiosis Confirmed by Polymerase Chain Reaction and Treated with Atovaquone and Azithromycin

Human babesiosis is a tick-borne infectious disease caused by Babesia species. The clinical diagnosis is difficult because of nonspecific symptoms like flu. Rapid diagnosis of human babesiosis is microscopic examination in peripheral blood smear (Giemsa-stain) which reveals characteristic forms of an intracellular quadruplet parasite. But differentiation between Babesia microti and Plasmodium species can be quite difficult because of the morphologic similarity. We experienced a case of human babesiosis. The patient was a 62-year old Korean male who had been in New Jersey, U.S.A for 2 months. We initially diagnosed as malaria infection because the peripheral blood smear revealed intracellular single ring form organism. But the patient was not improved significantly by the treatment with chloroquine regimen. Finally we confirmed human babesiosis by polymerase chain reaction for Babesia microti. We treated the patient successfully with a regimen of atovaquone and azithromycin which has fewer adverse reactions than a regimen of clindamycin and quinine.