| PurposeThe consumption of NSAIDs (non-steroidal anti-inflammatory drugs) is unparalleled by that of any other drug classes due to their great efficacy in the treatment of inflammation, pain and fever. Their therapeutic capacity owes to inhibiting the specific isoforms of COX (cyclooxygenase) that catalyzes the rate-limiting step in PGs (prostaglandins) biosynthesis. NSAIDs' side effects, such as mucosal lesions, perforation and bleeding, which often occur after chronical administration, are the main shortcoming which heavily limits NSAID's further clinical application.The present dissertation aims at reversaling NSAIDs-induced GI injury by means of inflammatory site-specific nano-DDS (nano-drug delivery system), which would be useful in decreasing the systemic dosage.RationaleThe pathologic changes, EPR effect (enhanced permeability and retention effect) happened at inflamed site, can be exploited to achieve targeting release. EPR effect means (1) the vasopermeability at the inflamed regions is greatly elevated, as a result the upper size limit of the permeable particles increases from 20nm (before inflammation) to 200nm (under inflammation), (2)the permeated particles could stay there for a longer time. Therefore, if NSAIDs are entrapped within nanoparticles, they can be directed to inflammation region and then be left there.This present study has prepared a series of nanoparticles, with KT (ketoprofen) as model drug, whose GI side-effect is of high grade, with soybean oil, triglyceride, or lecithin as carriers. It gives light into the factors affecting in-vivo site specificity of nano-DDS, such as pathology, drug or dosage form. Several interesting findings have been obtained.Pharmacokinetic-Pharmacodynamic ModelAfter injecting kT solution to mice with formaldehyde-induced paw edema via tail vein, it is found that the amount of KT in inflamed paw is more than twice that of the normal paw, implying KT to be intrinsically inflammatory site-specific. One possible explanation is that KT can be passively targeted to edema site via albumin since albumin has the chemotaxis towards inflammatory site and more than 99% of KT within circulation is bound to albumin. To confirm our assumption, acetaminophem which exerts no albumin-bonding ability, is tested on the same model. The outcome shows that the KT concentration ratio of inflamed paw over normal paw is around 0.8,satisfying our presumption.Although KT does have excellent inflammatory site-specific ability itself, there is still room to upgrade its utility, considering that it is more difficult for KT-HSA complex to transport cell membrane than KT alone, which is the indispensable step before KT's interacting with COX.Lipid nanospheres & Solid Lipid NanoparticlesFirst of all, we prepared lipid nanospheres (LN). To ensure sustained release, according to Mizhushima's report, KT octanol ester (KTO) and KT palmityl ester (KTP) are synthesized. Then, two esters' LN/SLN (blow 100nm) are gained with soybean oil as carrier, with Myrj 53 as stabilizer. Due to the hindrance of steric repulsion of Myrj, KT ester couldn't be degraded timely by esterase. Pharmacokinetic assay reveals that plasma and paw concentration of KT of LN/SLN are inferior to that of KT solution, so is pharmacodynamics. All these findings demonstrate that stealth modification is of little usefulness in this case.Subsequently, we study LN/SLN of KT (< 100nm), with soybean oil or tristearin as carrier, with oleic acid as release retarder, Myrj 53 as stabilizer. It is shown on mice that the LN/SLN display almost the identical pharmacokinetic behavior with kT solution does, but those oleic acid-containing LN/SLN exhibit more potent anti-inflammatory activity than KT solution (p<0.01), which may be contributable to the ability of oleic acid to enhance the transportation of KT across cell membrane. But, to our disappointment, haemolyticable oleic acid increases the acute toxicity of LN/SLN by 18 or 9 fold of KT respectively, limiting LN/SLN's would-be clinical application...
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