Multifunctional Magnetic Mesoporous Silica Nanoparticles For Anti-cancer Drug Delivery And Imaging

Cancer is a major public health problem. In the medication process oftumor therapy, a lot of anti-cancer drugs produce adverse effect to normaltissues when implementing the tumor suppressing role. Recently,nanomatrials have been considered as a promise tool for anti-cancer drugdelivery, which could relieve the possible side effects of drugs. On theother side, the complicacy of tumor tissues impede the application ofsingular drug for cancer therapy, and the recent stratagy is to combinemultiple drugs against different carcinogenic molecular targets to achievea better tumor inhibition effect. Moreover, the features of tumor tissues(e.g. the disorder distribution of tumor vessel systems, the invasion andmetastasis of tumor tissues) have pose challenges during cancerdiagnostics, and researchers hope that this challenge could be overcomeby applying functional nanomaterials. Therefore, developing propernanomaterials for combinational anti-cancer drug delivery and cancerdiagnosis is a requirement need to be resolved.In recent years, mesoporous silica nanoparticles (MSNs) have drawnmuch attention from biomedical researchers. Because of the excellentbiocompatibility, unique mesoporous structure, controllable particle sizeand pore diameter, MSNs have been becoming a promising drug carrierfor different diseases. In addition, MSNs were also found could be usedin imaging and diagnosis. Consequently, a lot of research has been published on the design and synthesis of functional MSNs for biomedicalapplications. On this basis, scientists have showed great interest onapplying MSNs for cancer therapy. MSNs are expected to overcomesome principal obstacles of current tumor therapy, including poor tumorspecificity and adverse effects of chemotherapeutics, combinationchemotherapy, diagnosis and prognosis, and so on. In this regard, thisthesis focuses on addressing the important issues of using MSNs fortumor therapy, namely, the exploration of multifunctional magneticMSNs (M-MSNs) on tumor combination therapy, using M-MSNs as aimaging vehicle, and developing new approach to increasing the tumortargeting efficiency.In the second chapter, we developed an approach for combinationtumor therapy by using M-MSNs as the carrier to load twodrug-combinations. We prepared M-MSNs with50nm in size; TEMcharacterization showed that the nanoparticles were composed ofmesoporous shell and10nm Fe3O4nanocrystal core. We studied theloading efficiency and behavior of three kinds of anticancer drugs, i.e.doxorubicin, paclitaxel and rapamycin. Our results demonstrated thatthese drugs could be efficiently loaded in M-MSNs with the loadingratios over15%. We also successfully loaded hydrophilic-hydrophobicdrug-pairs (doxorubicin-paclitaxel and doxorubicin-rapamycin) inM-MSNs, and found that in these combinations, the loading amount ofone single drug could impact that of the other drug, thus the drug ratiocould be tailored conveniently. Moreover, we found that the loaded drugscould be released from the vehicle, and achieve the target location inA549tumor cell. Tumor cell apoptosis and survival studies indicated thatthe co-loading fashion of multi-drugs could yield synergistic inhibitoryeffect to cancer cells. In the third chapter, we studied the impact of external magnetic fieldon cellular uptake of M-MSN. We found that the uptake of M-MSNscould be significantly enhanced by an external magnetic field, which wasa time-and concentration-dependent process. We then determined themechanism of magnetic enhanced uptake of M-MSNs. The resultssuggested that the uptake of M-MSNs on A549and MCF-7cells wasruled by a clathrin mediated endocytosis pathway. It’s worth noting thatmagnetic field did not change the endocytosis pathway but accelerate thedeposition of M-MSN to the surface of cells. By applying the magneticfield, the drug delivery efficiency of M-MSNs could also be increased.In the fourth chapter, the magnetic resonance imaging (MRI) abilityof M-MSNs was evaluated. We found that the MRI contrast enhancingability of M-MSNs, called relaxivity, achieved309mM/s, which is a veryhigh level. In order to determine the reason of the high relaxivity ofM-MSNs, we compared its relaxivity with non-porous magnetic silicananoparticles with the same size, and found the relaxivity of M-MSNs ismuch higher than non-porous silica nanoparticles, therefore indicated thatthe mesoporous silica shell play roles on the relative high relaxivity ofM-MSNs. We also studied the ex vivo imaging ability of M-MSNs ontumor cells and results showed that the nanoparticles could still producedetectable image contrast even cells amount was as less as25,000.In the last chapter, we explored a strategy to increase the tumortargeting ability of M-MSNs, which was based on using murine borrowderived mesenchymal stem cells (MSCs) as the delivering and targetingfacility. In the in vivo study, our results indicated that M-MSNs have highuptake efficiency and low cytotoxicity to MSCs. We also determined theimpact of M-MSNs to the biological functions of MSCs, which suggestedthat the migration and differentiation ability were not affected. We then established subcutaneous tumor models to evaluate the in vivodistribution of the M-MSNs. Through in vivo fluorescent imaging, wefound that the fluorescence of M-MSNs was mainly localized in liver andspleen. However, the tumor histological section results indicated thatM-MSNs loaded in MSCs could be clearly observed in tumor tissue,while non-loaded M-MSNs was not detected. The results imply that thepotential of applying MSCs as the carrier to enhanced the targeting abilityof M-MSNs.