Preparation,Formula Optimization And Antitumor Actions Of Mannitol Coupling Camptothecin Nanoparticles

Camptothecin(CPT)is a monoterpene indole alkaloids isolated from Camptotheca acuminata.It is a potent,broad spectrum antitumor agent that inhibits the activity of DNA topoisomerase I.Due to its poor solubility and stability and consequent delivery challenges,its clinical use is nevertheless limited.The purpose of this work is to prepare a formulation using mannitol coupling Camptothecin(CPT)nanoparticles(CPT-NPs)to circumvent the difficult solubilization practice.Firstly,we prepared the micro powder of Camptothecin by an anti-solvent method.The mean particle size of the Camptothecin micro powder is inferior to 1000 nm.Then,CPT-NPs were prepared with a high-pressure homogenization technique method.The independent variables considered for the optimization of CPT-NPs were percentage of CPT in raw material(CPT and mannitol),concentration of CPT in working liquid,cycles numbers and homogenizer pressure for drug loading efficiency,particle size and polydispersity index.Analysis of variance(ANOVA)statistical test was used to assess the optimization:The CPT-NPs were prepared by a high-pressure homogenization technique.In brief,25 mg mCPT was dispersed in deionized water(pH=6).The dispersion liquid was added to high-pressure homogenizer.Then after 12 cycles,2 mL aqueous solution of 100 mg mannitol was added dropwise to the CPT liquid in the high-pressure homogenizer.After 3 cycles,the mixed solution was lyophilized to obtain dry white powder.The optimized CPT-NPs showed an appropriate drug loading efficiency(18.09±2.13%),a homogeneous particle size(165.33±37.23 nm)and a low polydispersity index(0.29±0.01).The SEM image reveals that CPT-NPs are clavate and smooth.X-ray indicated that CPT-NPs is amorphously or disordered crystalline phase.It shows a significant difference between unprocessed CPT and CPT-NPs.The percentage of drug release was examined over time.The cumulative release of CPT is more than 70%within 72 hours.But unprocessed CPT exhibits a rapid release behavior and more than 99%of drug is released within 4 hours.These results suggest the CPT-NPs have a high controlled-release efficacy.The CPT-NPs group show higher inhibition ratio(79.95%)of H22 tumor growth in vivo compared with TPT and CPT at the same dose.Changes in mice body weight demonstrate CPT-NPs have the lower toxicity.The results of biodistribution studies indicated the obviously superiority of CPT-NPs in increasing the accumulation of CPT within tumor.Overall,CPT-NPs under optimum conditions are considered to be potentially feasible to overcome formulation challenges for drug delivery.