br cancer therapy The hypothesis has been
cancer therapy. The hypothesis has been proved by previous studies, which showed that a CD44-targeting HA-decorated bio-compatible oligomer containing Vitamin E and styrene maleic anhydride exhibits excellent triple-negative breast cancer tumor accumulation and selectively kills triple-negative breast cancer Suramin through the CD44-mediated apoptosis pathway, thus accom-panying with minimum liver and spleen uptake . On the basis of the above description, we believed that the current study on the design of nanodrug delivery systems would provide an effective strategy for the design of anticancer drugs used for treating triple-negative breast cancer.
Interestingly, in vivo anticancer studies demonstrated that [email protected] exhibited significant anticancer effects when compared to those of other drug forms including PAMAM-Dox and PAMAM-Pt-Dox. As shown in Fig. 5, [email protected] easily accumulated in tumors more than other nanodrug delivery systems such as stimuli-responsive polymeric nanogel  and Chitosan-W18O49 nanoparticles . More importantly, when compared with other nanodrug delivery systems, most [email protected] specifically accumulates in tumor tissues but not in other tis-sues. After treatment with [email protected], histological analysis showed that, except for the tumor, there were almost no changes in tissues including the heart, liver, spleen, lungs, and kidneys. Together, these results indicated that [email protected] was safe enough to be used in the clinic, which may be attributed to its cir-culation in the blood for a long time and its targeting effects, as HA reduced the potential of PAMAM and increased its size. Thus, the mechanism underlying the synergistic effect of the Pt-Dox combi-nation may be as follows: [email protected] enters the body through intravenous injection; then, [email protected] accumu-lates in the tumor by the targeting group HA. Further, [email protected] also accumulates in the liver and spleen because the liver and spleen are involved in detoxification and excretion activities. However, at 24 h after administration, [email protected] would be excreted from the body, except for the tumor site, thus suggesting the biosafety of [email protected] for clinical purposes. Although these findings are promising, the molecular mechanism involved in the in vitro and in vivo anti-cancer effect of [email protected] needs to be elucidated.
In the present study, a new type of PAMAM dendrimer deriva-tive was established. HA was used as the targeting group, and PAMAM was coated with Pt and Dox by a covalent reaction, which were found highly stable, biocompatible, and potent against breast cancer. This design enabled the synergistic killing of breast cancer cells. The dual drug-loaded [email protected] was found to be very stable and entered cells through the lysosome-mediate path-way. Cytotoxicity studies were employed in MCF-7 and MDA-MB-231 breast cancer cells, which indicated that [email protected] had a higher anticancer effect than that of monomers. In vivo tissue distribution studies of [email protected] demonstrated that [email protected] showed a remarkable increase in drug accumulation in the tumor tissue when compared with free drug solutions. Moreover, drug distribution studies indicated that after 24 h, almost no drugs were observed in the heart and kidneys, thus indicating that [email protected] may decrease side effects and increase antitumor effi-ciency. The in vivo antitumor efficacy data using MDA-MB-231 tumor-bearing BALB/c mice demonstrated that [email protected] had a stronger antitumor effect than other drug formulations. The present study demonstrated the co-delivery of Pt with Dox to achieve highly efficient ‘‘synergism” in breast cancer cells that may be extended to the other anticancer drugs.
Declaration of interest
The authors declare that there is no conflict of interest regard-ing the publication of this paper.
Appendix A. Supplementary data