Properties Of Carrier-Free Nano-Drug On Anticancer Efficiency For Overcoming Tumor Multidrug Resistance

Cancer is one of human diseases with the highest mortality rates in the world.Surgery,radiation therapy,chemotherapy and immunotherapy are the main methods for cancer treatment.However,current clinical approaches always face many challenges,such as toxic side effects on normal tissues,low drug accumulations at the tumor sites,and cancer recurrence caused by multidrug resistance(MDR).Recently,a plentiful of nanotechnology based nano-drug delivery systems are introduced to deliver drugs towards the tumor sites.Based on the current research achievements and the urgent problems to be solved in the clinical approaches,we have designed several carrier-free nano-drug systems in our previous work.The strategy of carrier-free nano-drug systems is based on self-assembly method,and its drug loading capacity can reach almost 100%.Attractively,when compared with nanocarriers based drug delivery systems,carrier-free nano-drug systems possess high drug loading capacity and excellent anti-cancer efficiency,reduced systemic toxicity and immunogenicity.At present,a series of studies have reported the physical and chemical properties effects of nanomedicine on the diagnosis and treatment efficacy of cancer,such as size,shape and surface charges,etc.However,different materials process different densities,hydrophobic properties and surface charges,and all these factors will lead to differences in the fate of nanomedicine when interacted with tumors.Therefore,we need to investigate materials specifically in the cancer research.To study the anticancer performance of carrier-free nano-drug with different size,a commonly used clinical chemotherapeutic drug,doxorubicin(DOX)was selected.We prepared DOX moleculars into three kinds of DOX nanoparticles with different sizes by changing experimental conditions of the solvent exchange method.DOX NPs(with size of 50 nm,100 nm,and 180 nm,respectively)were surface-modified with amphiphilic surfactants in order to achieve good biological environmental stability.We studied the in vitro release profiles,cellular uptake,cellular uptake mechanisms,in vivo blood circulation,biodistribution,and inhibitory effects on MDR cells of three DOX NPs with different sizes.The experimental results indicated that,DOX NPs with the size of 50 nm showed the highest cellular uptake and cytotoxicity.Moreover,DOX NPs with the size of 50 nm also show higher cytotoxicity than other two DOX NPs when incubated with MDR cells.In in vivo experiments,DOX NPs with the size of 50 nm presented the highest accumulation at the tumor site.Therefore,DOX NPs with the size of 50 nm possesses better anticancer effect than that of 100 nm and 180 nm.These results further confirm that carrier-free nano-drug process size effect on cancer treatment.We expect this work could provide a valuable reference to optimize the anticancer efficacy of carrier-free nano-drug.So far,the influence of surface roughness of nano-drug on the cellular fate has not yet been reported.Therefore,7-ethyl-10-hydroxycamptothecin(SN-38),a commonly used anticancer chemotherapeutic drug,has been selected to investigate the surface roughness effect of carrier-free nano-drug.By changing experimental conditions and the concentrations of the reagents in the solvent exchange method,two kinds of SN-38 NPs,similar by size and shape,but with different surface roughness,were prepared.Subsequently,we studied the effects of two SN-38 NPs(one with a relatively smooth surface,the other with a relatively rough surface)on cytotoxicity,cellular uptake,intracellular distribution and cellular uptake mechanisms.The results showed that the cellular uptake and cytotoxicity of the rough surface SN-38 NPs was higher than that of the smooth surface SN-38 NPs.However,the differences between two SN-38 NPs were not significant,this may be due to their different cellular uptake mechanisms.Overall,experimental results used in this study indicate that the surface roughness of NPs would influence the interaction between NPs and cancer cells to a certain extent.MDR in malignant tumors and adverse side effects of chemotherapeutic agents seriously hinder effective chemotherapy against cancer.To address these problems,we design a nanomedicine composed of pure doxorubicin(DOX)as the core and B-cell lymphoma-2(Bcl-2)siRNA on the surface for synergistic cancer treatment.Bcl-2 siRNA is a gene drug which would silence Bcl-2 anti-apoptotic proteins and thereby promote cancer cell apoptosis.Attractively,DOX@siRNA NPs is more likely to release drugs in acidic tumor environment,thereby reducing damages in the surrounding healthy cells and tissues.DOX@siRNA NPs result in stronger cytotoxicity than individual DOX NPs and Lipo-siRNA in cancer cells,exhibiting synergistic anticancer efficacy.In addition,DOX@siRNA NPs can effectively enter and kill DOX resistant MCF-7 cancer cells.Most notably,DOX@siRNA NPs exhibit significantly extended blood circulation half-life,high tumor accumulation and significant tumor growth inhibition.Overall,this method is able to achieve synergistic anticancer efficacy in tumor treatment and overcome drug resistance.We expect that this approach possesses significant potential for clinic applications.