Tri-partite complex for axonal transport drug delivery achieves pharmacological effect

Background

Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior.

Results

We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle.

Conclusion

Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise. The data shown here provide a basic framework for the intraneural pharmacology of this tripartite complex. The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.     

Top Quark Flavor Changing Decay t

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Physics beyond Standard Model: Working group 3 report

This is a summary of the beyond the Standard Model (including model building) working group of the WHEPP-X workshop held at Chennai from January 3 to 15, 2008. Participants: Neelima Agarwal, S K Agarwalla, C S Aulakh, A Belyaev, S S Biswal, B Bhattacharjee, G Bhattacharyya, L Calibbi, D Choudhury, E J Chun, D Das, A De Roeck, N G Deshpande, E Dudas, A Giri, D Grellshceid, R Godbole, S Goswami, M Guchait, M Hirsch, R Kaul, B Kodrani, M C Kumar, A Kundu, Y Mambrini, P Mathews, B Mellado, R Mohanta, S Mohanty, A Nyffeler, S Pakvasa, M K Parida, M Passera, C Petridou, S Poddar, P Poulose, A Rajaraman, G Rajasekaran, V Ravindran, Kumar Rao, D P Roy, Probir Roy, K A Saheb, V H Satheeshkumar, T Schwetz, A Tripathi, R Vaidya and S Vempati     

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高温高压下材料的本构模型

 在SCG模型基础上对其温度软化效应项作了改进,所提出的新模型在熔点温度T_m处满足剪切模量G(T_m)=0,从而提高了温度的适用范围。对Al和93W作了计算,其理论结果与实验符合相当好。     

Charge transfer via a two-strand superexchange bridge in DNA

Charge transfer in a DNA duplex chain is studied by constructing a system with virtual electrodes connected at the ends of each DNA strand. The system is described by the tight-binding model and its transport is analyzed by the transfer matrix method. The very weak distance dependence in a long (G:C)(T:A)M(G:C)3 DNA chain observed in experiment [B. Giese, Nature (London) 412, 318 (2001)] is explained by a unistep two-strand superexchange bridge without the need for the multistep thermally induced hopping mechanism or the dephasing effect. The crossover number Mc of the (T:A) base pairs, where crossover between the strong and weak distance dependence occurs, reflects the ratio of intra- and interstrand neighboring base-base couplings.     

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Ultrasound thrombolysis

Ultrasound energy for thrombolysis dates back to 1976. Trubestein et al. demonstrated first in vitro that a rigid wire delivery low frequency ultrasound energy could disrupt clot. These investigators also showed that this system had potential for peripheral arterial clot dissolution in vivo in animal studies [G. Trubestein, C. Engel, F. Etzel, Clinical Science 51 (1976) 697s-698s]. Subsequently, four basic approaches to ultrasonic thrombolysis have been pursued - two without pharmacological agents: (1) catheter-delivered external transducer ultrasound, (2) transcutaneous-delivered HIFU external ultrasound without drug delivery and ultrasound in conjunction with thrombolytic drugs and/or microbubbles or other agents, (3) Catheter-delivered transducer-tipped ultrasound with local drug delivery, and (4) transcutaneous-delivered low frequency ultrasound with concomitant systemic (intravenous) drug delivery for site specific ultrasound augmentation. This article reviews recent data on therapeutic ultrasound for thrombolysis in vitro, in vivo, in animal studies, as well as in human clinical trials.