br nutrient deprivation a growing body
nutrient deprivation, a growing body of evidence revealed that autophagy plays an inhibitory role in the process of tumor for-mation, suggesting that autophagy may be an excellent mecha-nism for tumor suppression21. Although the anti-tumor efficacy of RAP combined with PTX in breast cancer has been verified in preclinical and clinical trials, the relationship between autophagy and synergistic effect of this combined strategy is not well un-derstood, despite the effectiveness of RAP in induction of ACD.
It’s worth noting that the clinical outcome of current combi-nation therapy based on conventional pharmaceutical preparations is unsatisfactory, due to the short half-lives of chemotherapeutic agents and lack of distribution selectivity, leading to severe side effects and deficient therapeutic efficacy22. Nanotechnology-based targeted delivery systems provide good opportunity to address the associated problems and provide superior therapeutic benefits23. Some antitumor nanomedicines, such as Doxil (PEGylated liposomal doxorubicin) and Abraxane (PTX (PTX) loaded al-bumin nanoparticles), have been approved by FDA for more than 10 years24. Nanomedicines can selectively deliver cargos to cancerous LY3009120 through passive targeting based on enhanced permeation and retention (EPR) effect, as well as active mecha-nisms based on molecular recognition between the overexpressed receptor/antigen on cancerous cells with the targeting molecules on the surface of nanocarriers25. Transferrin receptor (TfR) is overexpressed in various cancer cells, making it an excellent target for tumor recognition. 7pep (7pep, Histidine-Alanine-Isoleucine-Tyrosine-Proline-Arginine-Histidine, HAIYPRH) is a peptide obtained through phage display and has exhibited high affinity to TfR. Thus, 7pep can serve as an effective ligand for cancer-targeted drug delivery systems26,27.
Therefore, based on the above background, we developed a 7pep-modified dual-nanomedicines system that loaded RAP and PTX separately to examine the efficacy and safety in the treatment of breast cancer, while focusing on the role of RAP-induced autophagy in the combined anti-tumor efficacy. It is expected that the dual-nanomedicines administered in combination can actively accumulate in tumor sites via TfR-mediated mechanism and achieve favorable anti-tumor effect compared to monotherapy. It is well known that the nanomedicine has a great influence on pharmacokinetics, such as drug release, absorption, and distribu-tion behavior28, but underlying anti-tumor mechanism of co-administration of nanomedicines has been rarely reported. In particular, autophagy is a dynamic process that correlates with cellular status, drug concentration, administration schedule and sequence, Prion is necessary to explore the role of autophagy in the synergic effect of dual-nanomedicines in combination. Firstly, a functional material with TfR targeting ability was synthesized through the conjugation of 7pep to PEG-DSPE copolymer, and
Please cite this article as: Mei D et al., Actively priming autophagic cell death with novel transferrin receptor-targeted nanomedicine for synergistic chemotherapy against breast cancer, Acta Pharmaceutica Sinica B, https://doi.org/10.1016/j.apsb.2019.03.006
Priming autophagic cell death with transferrin receptor-targeted nanomedicine 3
then functional nanocarriers were constructed by a solvent evap-oration method. The active targeting efficacy of nanocarrier, su-perior autophagy inducibility of 7pep-RAP-M, anti-proliferation and pro-apoptotic effects of functional nanocarriers used alone or in combination in a human breast cancer cell line (MCF-7) were evaluated, followed by the in vivo distribution, antitumor efficacy and toxicity studies. Especially, the probable mechanisms involved with this strategy of dual-nanomedicines were well explored.