Co-delivery of cisplatin and doxorubicin by covalently conjugating with polyamidoamine dendrimer for enhanced synergistic cancer therapy

Abstract

Because of the synergistic effects of drugs and minimal drug dose for cancer therapy, combination chemotherapy is frequently used in the clinic. In this study, hyaluronic acid-modified amine-terminated fourth-generation polyamidoamine dendrimer nanoparticles were synthesized for systemic co-delivery of cisplatin and doxorubicin (HA@PAMAM-Pt-Dox). In vitro data showed that HA@PAMAM-Pt-Dox can enter the cells through the lysosome mediated-pathway in a time-dependent manner. Cell viability studies indicated that HA@PAMAM-Pt-Dox exhibited a higher anticancer activity on MCF-7 and MDA-MB-231 breast cancer cells at a relative low concentration. HA@PAMAM-Pt-Dox not only efficiently inhibited tumor growth but also significantly reduced the toxicity of Dox. Moreover, intravenous administration of HA@PAMAM-Pt-Dox to MDA-MB-231 tumor-bearing BALB/c nude mice resulted in the accumulation of HA@PAMAM-Pt-Dox at the tumor site, thereby significantly inhibiting tumor growth without apparent toxicity. These results suggested that HA@PAMAM-Pt-Dox has great potential to improve the chemotherapeutic efficacy of cisplatin and doxorubicin in breast cancer. Statement of SignificanceOne of the main problems in cancer treatment is the development of drug resistance. To date, it is believed that combination chemotherapy might be an effective strategy for the above problem. However, for two completely different drugs, combination chemotherapy faces huge difficulties including the antagonistic nature of drugs, variations in drugs in terms of solubility, and limited tumor targeting. Recent developments in nanoscience and nanotechnology provide an effective approach for such disadvantages. Considering the advantages of dendrimers such as control of size and molecular weight, bioavailability, and biosafety, we used fourth-generation dendrimers modified by HA as drug vectors by covalently conjugating them with anticancer drugs (cisplatin and doxorubicin) to form a nanodrug delivery system, named HA@PAMAM-Pt-Dox. We observed that the HA@PAMAM-Pt-Dox system can effectively kill breast cancer cells both in vitro and in vivo, which showed a favorable synergistic effect. This strategy can be extended to other drugs, thus providing a highly effective strategy for cancer treatment.