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Preparation and Function of Nanocerasomes for Diagnosis and Therapy of Cancer

Author: LiangXiaoLong
Tutor: DaiZhiFei
School: Harbin Institute of Technology
Course: Biomedical instrumentation and engineering
Keywords: Cerasomes controlled release photodynamic therapy magneticresonance imaging theranostic agents
CLC: R318.08
Type: PhD thesis
Year: 2012
Downloads: 4
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Abstract

Cancer is a threat disease to human health and survival, for a long time, themajority of researchers have been continuing to explore and develop a variety oftreatment methods, drug delivery is an important one, because it can effectivelyprevent drug degradation, transport drug to the lesions, reduce toxicity and increasetherapeutic effect. However, with the development of the times, the traditional drugcarriers gradually revealed some shortcomings, such as poor stability, poorbiocompatibility, low drug loading efficiency, less enrichment in targeting tumor andshort circulation time in vivo, these problems greatly reduce the bioavailability ofdrug and increase the suffering of patients, therefore, there is an urgent need todevelop new drug carriers. Currently, the drug carrier is toward in the direction ofcontrolled, intelligent, green and theranostic, developing a variety of new carrierswith good prospects. Organic-inorganic hybrid material is one of them, whichcombines the characteristics of organic and inorganic materials, possessing uniqueadvantages. In this paper, an organic-inorganic hybrid materials–Cerasome wasused as the main object of study, with the view point of molecular design for theorganic-inorganic hybrid lipid, systematic research in the structure-controlledrelease, light-controlled release, photodynamic therapy, and photodynamic therapycombined with magnetic resonance imaging were carried out.The relationship between the hybrid lipid structure and drug release properties ofCerasome was researched. By adjusting the ratio of hydrophilic and hydrophobicgroups in the lipid molecules, four lipids with different structures were synthesized,later sol-gel and self-assembly technologies were applied to obtain four newCerasomes with silicate network of different surface density. Hydrophilic drugdoxorubicin and hydrophobic drug paclitaxel were used as the model drug, four kindsof doxorubicin-Cerasomes and paclitaxel-Cerasomes were successfully prepared. Invitro drug release behavior and cytotoxicity results showed that the release propertiesof drug carriers were closely related with structure of the corresponding lipids. Allthe carriers can release the drug slowly, with the same hydrophobic groups, thehigher number of hydrophilic silane group, the slower release rate of the drug. Incontrast, with the same hydrophilic silane groups, the more the hydrophobic groupresulted in the faster release rate of hydrophilic drug and the slower release for thehydrophobic drug. Cell experiments showed that the inhibition effect of the drugloaded Cerasomes were consistent with their drug release behavior, that is to say,with the same drug concentration and incubation time, the faster drug release from the carriers lead to more obvious inhibitory effect on cells. These results fully reflectthe design of the molecular structure can effectively regulate the permeability of theCerasome bilayer.Highly stable and sensitive light-responsive material for controlled drug releasehad been studied. Photosensitive azobenzene group was introduced into the hybridlipid by organic synthesis to obtained a new type of photoresponsive organic-inorganic hybrid lipid, thus light-responsive vesicle with azobenzene lipid bilayerwas prepared. Photo-isomerization of the azobenzene unit in the vesicles wasdetected by UV-visible absorption spectra, affecting factors to the photo-isomerization was clarified. The results showed that the azobenzene group anddouble-chain were mainly distributed in the vesicle bilayer with an alternative mode.With alternative irradiation by UV and visible light, the azobenzene group canachieve a reversible configuration conversion, and its trans-isomerization ratio was33.4%. Nile red was use as a model drug to study the photo controlled-releaseperformance of the carrier. The study found that upon UV light irradiation, the carriercan released Nile red of48.2%in20min, showing the sensitive capabilities of light-controlled drug release.Cerasome with fluorescence and photodynamic function was developed. Theintroduction of the porphyrin groups to the hybrid lipid resulted in a new hybrid lipidcontaining double-chain, porphyrin and silane head groups, the correspondingporphyrin Cerasome used as photodynamic agents were then prepared, its drug-loaded efficiency could reach to33.4%. The vesicular structure of porphyrinCerasome was verified by encapsulation a hydrophilic dye of calcein. A lot ofexperiments combined with discussion and analysis were carried out to study theaggregation and arrangement mode of the porphyrin groups, the important role ofchemical covalent bonded with porphyrin groups, singlet oxygen generatedefficiency and mechanism, and cellular uptaken way. Observation on cellmorphology and MTT assay were applied to test the photodynamic effect, finallypreliminary animal experiments were carried out to study the blood circulationdynamics of the carrier in rat. The results showed that double-chain and porphyrinunit should mainly arrange in an orderly alternating manner, so aggregation ofporphyrin unit in the Cerasome did not exist, upon UV light irradiation, the carriershowed brightly red fluorescence. Porphyrin Cerasome can significantly generatedsinglet oxygen in heavy water and cancer cells, and singlet oxygen generatedefficiency was proportional to the carrier concentration and light irradiating time.Confocal laser scanning microscopy images clearly showed porphyrin Cerasome wasuptaken by tumor cells through an endocytosis way, and mainly located in the lysosome. The vesicle exhibited low dark toxicity and significant phototoxicity to thecells, and it could maintain a long circulating time in the blood, showing thesignificant advantage as drug carrier.Theranostic nanoparticle simultaneously with photodynamic therapy and magneticresonance imaging abilities was design and prepared. Based on the synthesis in theprevious chapter, the porphyrin and manganese porphyrin derivatives were combinedtogether to obtain a new kind of nanoparticles with inside double-porphyrin bilayerand outside manganese porphyrin, in which inside porphyrin was for photodynamictherapy, the outer layer of manganese porphyrin was for magnetic resonance imaging.Studies for such particles were carried out, including preparation method,spectroscopic properties, singlet oxygen generated efficiency, cellular uptaken, invitro magnetic resonance imaging and photodynamic therapy testing. Experimentalresults showed that the nanoparticles showed obvious core-shell structure in TEM.By adjusting the ratio of the outer manganese porphyrins, five different nanoparticleswith adjustable photodynamic effect and magnetic resonance imaging can beprepared. The more proportion of manganese porphyrin led to the higher acceleratedlongitudinal relaxation efficiency of water proton, the ratio of higher than40.1%canresulted in the best imaging results. Cell experiments confirmed that thenanoparticles can be effectively uptaken by tumor cells and showed low dark toxicityand high phototoxicity, the ultimate nanoparticles to meet the imaging andphotodynamic therapy effect was the one with manganese porphyrins ratio of40.1%.

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