Investigation On The In Vivo Pharmacokinetics And Antitumor Activity Of Platelet-camouflaged Thermo-Chemotherapeutic Nanoagent

RGD-NPVs@MNPs/DOX,a nanoagent with synergetic chemo-photothermal therapy was fabricated by our group by loading natural melanin nanoparticles and doxorubicin into RGD peptide-modified platelet membrane vesicles.Our previous in vitro study showed that the prepared nanoagent can actively target drug-resistant MDA-MB-231/ADR breast cancer cells,can escape from macrophage phagocytosis,and can reverse the drug resistance of MDA-MB-231/ADR cells by thermogenesis under near-infrared laser irradiation,and exhibited a good synergistic inhibition on MDA-MB-231/ADR cells by a combined chemothermotherapeutic effect.Based on the finding by previous in vitro studies,in this study,we further investigated the pharmacokinetics,anti-tumor effect and biological safety of RGD-NPVs@MNPs/DOX in vivo.Pharmacokinetic study revealed that RGD-NPVs@MNPs/DOX could avoid the phagocytosis of macrophages in MDA-MB-231/ADR tumor-bearing nude mice due to the CD47 protein on the surface of platelet membrane,the nanoagent this preparation had a long blood circulation time and a half-life of 26.4:±3.2 h.Using RGD peptides modified on the surface of platelet membranes,RGD-NPVs@MNPs/DOX can specifically bind to the over expressed ?v?3 integrin on MDA-MB-231/ADR cells and tumor endothelial cells,leading to an active dual targeting to tumor cells and tumor vessels.In vivo anti-tumor studies showed that RGD-NPVs@MNPs/DOX can simultaneously act on tumor cells and tumor blood vessels under the irradiation of near-infrared laser,which has a better combined therapeutic effect of thermochemotherapy and can effectively inhibit the growth of drug-resistant tumors.Compared with the PBS group,the tumor volume of the RGD-NPVs@MNPs/DOX+laser group was only 20 mm3 after 22 days of treatment,indicating a more effective tumor inhibition.By inhibiting both tumor cells and tumor vessels,the metastasis of MDA-MB-231/ADR cell to mouse lungs was significantly inhibited.Blood physiological and biochemical test results showed that RGD-NPVs@MNPs/DOX mice were safe after injection.By histopathaological section observation,we found that RGD-NPVs@MNPs/DOX did not cause damage to the liver,heart,spleen,lungs,kidneys of mice after injection.These results indicate that RGD-NP Vs@MNPs/DOX is safe and less toxic.