Biotoxicity And Biocompatibility Of The Typical Nanoparticle C60

Nanomedicine, the application of nanotechnology to medicine, enables the developmentof nanoparticle therapeutic carriers. These drug carriers are passively targeted to tumorsthrough the enhanced permeability and retention effect, so they are ideally suited for thedelivery of chemotherapeutics in cancer treatment. Indeed, advances in nanomedicine haverapidly translated into clinical practice. Fullerenes，as a typical nanoparticle, have uniquephysical and chemical properties. In recent years, studies on functionalized fullerenes forvarious applications in the field of biomedical sciences have seen a significant increase. Theultimate goal is towards employing these functionalized fullerenes in the diagnosis andtherapy of human diseases. It is worth to note that nanomaterials’ safety has caused widepublic concern with more studies on nanontoxicities. The key problem is to understand basicbiological behavior and mechanisms of nanomaterials. Thus, it is important to constructreliable models of nanoparticles to create a nanomaterial system of biological safetyevaluation at gene, cell and systemic levels. Main contents and results are as follows:(1) Molecular dynamics (MD) simulations combined with celluar experiments werecarried out to investigate the interactions of the multidrug resistance (MDR) protein P-gp withfullerene (C60). Upon exposure to fluorescence-labeled C60(0–70mgmL-1) for2h,significant accumulation of C60is found in both K562S (MDR cells) and K562R (drug-sensitive cells), suggesting the incapability of P-gp to induce the efflux of this nanoparticle.In addition, in vitro inhibition assays also reveal that C60does not obviously hinder P-gp-mediated rhodamine-123transport in both K562S and K562R cells. The theoreticalsimulations further reveal the mechanism involved in C60-P-gp interactions, i.e., the bindingof C60barely induces the conformational changes of P-gp with RMSD of~4.8and radius ofgyration of~41.5. These results demonstrate the potential of C60as a good carrier candidatefor MDR-targeted drug delivery.(2) Using an examination of2254native nucleotides with geometry-based algorithm,MD simulation and thermodynamic analysis, we analyzed and evaluated how the DNA/RNAnative structures are disrupted by C60in a physiological condition. The nanoparticle wasfound to bind with the minor grooves of double-stranded DNA and trigger unwinding anddisrupting of the DNA helix, which indicates C60can potentially inhibit the DNA replication.In contrast to that of DNA, C60only binds to the major grooves of RNA helix, whichstabilizes the RNA structure or transforms the configuration from stretch to curl. This findingsheds new light on how C60inhibits reverse transcription as HIV replicates. In addition, the binding of C60stabilizes the structures of RNA riboswitch, indicating that C60might regulatethe gene expression. The binding energies of C60with different genomic fragments varies inthe range of-56to-10kcal mol-1, which further verifies the role of nanoparticle in DNA/RNAdamage. Our findings reveal a general mode by which C60causes DNA/RNA damage orother toxic effects at a systematic level, suggesting it should be cautious to handle thesenanomaterials in disease therapy.(2) MD simulation method, radial distribution function and Radius of gyration wasapplied to study the interactions of C60and its three typical derivatives (the negativelycharged with–COOH groups (C60-B), positively charged with-NH3+groups (C60-C) and theno charged with–OH groups (C60-D)) with two important blood lipids, cholesterol (CHL)and triglyceride (TGL). The simulation results indicate that:(1) the four fullerene moleculesenable to form aggregates in silico blood respectively, which do not cause significantdifference in aggregate size dispite of different surface modifications for the nanoparticles;(2)CHL enhances the aggregation degree of particles C60and charged C60-B and C60-C.However, CHL causes the self-aggregation of no charged C60-D due to the steric repulsionbetween the CHL and the–OH groups on the surface of C60-D.(3) TGL strengthens theaggregation degree of C60, negatively charged C60-B and no charged C60-D. But TGLenhances the distribution degree of positively charged C60-C due to the long chain packing ofTGL for each C60-C. The results show these fullerene molecules influence the behaviors ofblood lipids, which is important for human health, and thus, require careful utilization of C60molecules as drug carriers.Although C60shows a significant advantage to overcome MDR, our recent study alsoindicates that C60probably causes gene toxicity, and represents negative effects for thedynamic behaviors of blood lipids, suggesting the potential side effects of C60on the diseasediagnosis and therapy. Meanwhile, our work creats a novel system to evaluate the biologicalsafety of nanoparticles at gene, cell and systemic levels.