Cocktail Strategy Based on Spatio‐Temporally Controlled Nano Device Improves Therapy of Breast Cancer

• Published in: Advanced materials (Weinheim) 2019-02, Vol.31 (5), p.e1806202-n/a
• Main Authors: Lang, Tianqun, Liu, Yiran, Zheng, Zhong, Ran, Wei, Zhai, Yihui, Yin, Qi, Zhang, Pengcheng, Li, Yaping
• Format: Article
• Language: English
• Subjects: Animals; Anticancer properties; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cancer; cancer stem cells; Cell Survival - drug effects; Chemotherapy; Drug carriers; Drug Carriers - chemistry; Drug delivery systems; Drug Therapy, Combination; Female; Humans; immunotherapy; Infiltration; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Lymphocytes; Matrix Metalloproteinase 9 - pharmacology; Matrix Metalloproteinase 9 - therapeutic use; MCF-7 Cells; Mice; Micelles; nano device; Nanoparticles; Nanoparticles - chemistry; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Paclitaxel - chemistry; Paclitaxel - pharmacology; Paclitaxel - therapeutic use; Particle size; Pharmacology; Stem cells; Strategy; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Thioridazine - chemistry; Thioridazine - pharmacology; Thioridazine - therapeutic use; Transplantation, Heterologous; Tumors
• ISSN: 0935-9648; 1521-4095
• DOI: 10.1002/adma.201806202

Metastatic breast cancer may be resistant to chemo‐immunotherapy due to the existence of cancer stem cells (CSC). Also, the control of particle size and drug release of a drug carrier for multidrug combination is a key issue influencing the therapy effect. Here, a cocktail strategy is reported, in which chemotherapy against both bulk tumor cells and CSC and immune checkpoint blockade therapy are intergraded into one drug delivery system. The chemotherapeutic agent paclitaxel (PTX), the anti‐CSC agent thioridazine (THZ), and the PD‐1/PD‐L1 inhibitor HY19991 (HY) are all incorporated into an enzyme/pH dual‐sensitive nanoparticle with a micelle–liposome double‐layer structure. The particle size shrinks when the nanoparticle transfers from circulation to tumor tissues, favoring both pharmacokinetics and cellular uptake, meanwhile achieving sequential drug release where needed. This nano device, named PM@THL, increases the intratumoral drug concentrations in mice and exhibits significant anticancer efficacy, with tumor inhibiting rate of 93.45% and lung metastasis suppression rate of 97.64%. It also reduces the proportion of CSC and enhances the T cells infiltration in tumor tissues, and thus prolongs the survival of mice. The cocktail therapy based on the spatio‐temporally controlled nano device will be a promising strategy for treating breast cancer. An enzyme/pH dual‐sensitive nanoparticle with a micelle–liposome double‐layer structure, named PM@THL, shows spatio‐temporally controlled particle size and drug release when applied for breast cancer therapy. PM@THL intergrades immune checkpoint blockade therapy and chemotherapy against both bulk tumor cells and cancer stem cells, and exhibits significant anticancer and lung metastasis suppression efficacy.