Fabrication And Anti-tumor Research Of Au Nanorods-based Drug Delivery Systems

Malignant tumor seriously threatens the health and life of human,and breast cancer exerts the highest fatality rate in female patients.Anti-breast cancer effect of chemotherapeutic drug?e.g.doxorubicin?DOX??in clinic has often been compromised by the occurrence of multidrug resistance?MDR?,resulting in chemotherapy failure and cancer patient death.Au nanorods?AuNRs?have gained wide attention in cancer diagnosis and therapies based on their unique optical property of converting light to local heating under near-infrared?NIR?laser irradiation in the biological window?700-900 nm?.Tumor photothermal therapy?PTT?and photodynamic therapy?PDT?are curative and noninvasive light-triggered tumor treatment modality based on phototherapeutic agents and external light.But the applications of phototherapeutic agents in cancer treatment are seriously limited by the poor photostability and bad cancer targeting.Therefore,three kinds of AuNR-based nano-sized drug delivery systems?DDSs?were developed for anti-tumor research:?1?a pH-responsive AuB@D-DOX/PND nanocomplex for treating MDR cancer,?2?a glutathione detonated and pH responsive AuNR Cluster for treating MDR cancer,?3?a?ICG/AuNR?@SL nano-system with PTT-PDT effect for treating cancer.First,a pH,redox and NIR photothermal tri-responsive AuNR-based nanocomplex was constructed for co-delivery of chemotherapeutic agent DOX and chemosensitizer pyronaridine?PND?to treatment MDR MCF-7/ADR cells.DOX and PND were firstly intercalated inside the pH-responsive double-stranded DNA?dsDNA?,obtaining dsDNA-DOX/PND with negative surface potential.Then,dsDNA-DOX/PND was further complexed with positive charged biotin/PEGylated disulfide-linked polyethylenimine functionalized AuNRs?AuNR-SSPEI-PEG-Biotin?via electrostatic interaction to develop the DOX and PND co-loaded multifunctional nanocomplex?AuNR-SSPEI-PEG-Biotin@dsDNA-DOX/PND,AuB@D-DOX/PND?.The results of stability,hemolysis and erythrocyte aggregation assays proved that AuB@D-DOX/PND had good stability and hemocompatibility.The nanocomplex could responsively release the payload drug under intracellular GSH concentration?5 mM?,acidic pH?⁵?,and/or 808 nm NIR laser irradiation.In flow cytometry,enhanced cellular uptake and potent inhibition of DOX efflux by MCF-7/ADR cells for AuB@D-DOX/PND group were observed than that for free DOX group,and NIR laser could be served as a remotely trigger to bost the intracellular drug release.The nanocomplex had greatly increased cytotoxicity to MDR MCF-7/ADR cancer cells than free DOX(IC₅₀,6.21:70.68?g/mL).When combined with NIR laser irradiation,the DOX release from the nanocomplex was improved and the anti-tumor effect of the nanocomplex was ehanced(IC₅₀:2.88?g/mL).The tri-responsive nanocomplex presented significantly increased toxicity on MDR cancer cells,which is²0 fold on that for free DOX.Consequently,this nanocomplex is an effective strategy for treating MDR cancer.Then,a glutathione detonated and pH responsive nano-cluster of AuNRs with chemotherapeutic DOX and pre-chemosensitizer polycurcumin?PCDA?was fabricated for treating MCF-7/ADR cancer cells.pH-responsive DOX and poly?curcumin-co-dithiodipropionic acid?-b-biotinylated poly?ethylene glycol??PCDA-PEG-Biotin?were conjugated on AuNRs via Au-S bond to get the amphiphilic individual DOX-AuNR-PCDA-PEG-Biotin,termed AuNR.And then,the nano-cluster was prepared by self-assembling of individual AuNR via an emulsion/solvent evaporation technique,termed AuNR Cluster.AuNR Cluster with a high DOX dose?31.5%?exerted much better aqueous solubility and stability at physiological pH,higher photothermal effects under NIR laser irradiation than the individual AuNR.AuNR Cluster were detonated to be the individual AuNR at an GSH concentration?5 mM?in intra-cell and triggered to release DOX at an weak acid pH?6.8 or 5.0?.AuNR Cluster had improved celluar uptake and inhibited DOX efflux than free DOX.In comparison with individual AuNR,AuNR Cluster possessed much effective cellular uptake of DOX,and the fluorescence intensity were 607 a.u.for AuNR Cluster and 356 a.u.for AuNRs at 12 h respectively.AuNR Cluster presented a lower IC₅₀ value of DOX against MCF-7/ADR cells than that for free DOX?4.15 vs 90.97?g/mL?and much enhanced anti-tumor effect(IC₅₀:2.61?g/mL)under a 808 nm NIR laser irradiation.AuNR Cluster could play a role of inspiring the development of DDSs.Finally,the AuNR as a photothermal conversion agent and the indocyanine green?ICG?as a photosensitizer co-deliveried sophorolipid?SL?nano-system,termed as?ICG/AuNR?@SL,was fabricated via an emulsion/solvent evaporation method for synergetic NIR-triggered photothermal-photodynamic therapy?PTT-PDT?of 4T1cancer cells.The?ICG/AuNR?@SL had improved stability and photothermal effect,which effectively facilitated cellular uptake of ICG?2.6 times of free ICG at 3 h?and intracellular ROS generation?71.2 vs 33.0 a.u.for free ICG?.In vitro NIR laser induced cytotoxicity test,?ICG/AuNR?@SL exhibit significantly reduced cell survival than free ICG at the same concentration under the 808 nm NIR laser irradiation.And there is almost no killing effect on 4T1 cells for the control group without NIR laser irradiation.Taken together,the ICG and AuNR co-encapsulated nano-sized system was an effective phototherapeutic agent for combating cancer cells via NIR-mediated synergetic PTT-PDT therapy.In summary,a pH,redox and NIR photothermal tri-responsive AuNR system was firstly prepared for intracellular co-delivery of DOX and PND to combat MDR MCF-7/ADR cells.Then,AuNR Cluster,a nano-cluster of AuNRs conjugated with chemotherapeutic and pre-chemosensitizer,was successfully prepared and had bigger cytotoxicity against MCF-7/ADR cells than its individual AuNR,and this AuNR Cluster is a potential nano-system for cancer treatment.Finally,AuNR was as a photothermal conversion agent and co-encapsulated with photosensitizer ICG in SL nano-system for NIR-mediated PTT-PDT therapy of 4T1 cancer cells.These AuNR-based nano-sized DDSs have potential applications for treating cancer via NIR-controlled chemotherapy or NIR-mediated PTT-PDT.