Research Article: Mutual Destruction of Deep Lung Tumor Tissues by Nanodrug‐Conjugated Stealth Mesenchymal Stem Cells

Date Published: February 26, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Sang‐Woo Kim, Yeon Kyung Lee, Jeong Hee Hong, Jun‐Young Park, Young‐Ae Choi, Dong Un Lee, Jungil Choi, Sun Jin Sym, Sang‐Hyun Kim, Dongwoo Khang.

http://doi.org/10.1002/advs.201700860

Abstract

Lung cancer is a highly malignant tumor, and targeted delivery of anti‐cancer drugs to deep lung tumor tissue remains a challenge in drug design. Here, it is demonstrated that bone marrow mesenchymal stem cells armed with nanodrugs are highly targeted and mutually destructive with malignant lung cancer cells and successfully eradicate lung tumors tissues. Using this approach, the current clinical dose of anti‐cancer drugs for the treatment of malignant lung tumors can be decreased by more than 100‐fold without triggering immunotoxicity.

Partial Text

The 10‐year survival rate of cancer patients has greatly increased over the last 20 years.1 However, the survival rate of patients with major malignant tumors, such as lung and pancreatic cancers, still shows negligible improvement.1 The conventional chemotherapeutic strategy for treating lung cancer remains unsatisfactory in this respect. Specifically, the 5‐year survival rates of both non‐small‐cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients exhibited merely 4–5% improvements in the past decade for cancer in stages I–III.2 The main difficulty in treating lung cancer is the lack of targeted chemotherapeutic agents specific to the lung tumor tissues and, thus, non‐specific targeting generally leads to unwanted side effects induced by excessive doses of chemotherapeutic agents.3

The stem cell therapy market already possesses several FDA‐approved products. Authorized therapies include the treatment for autoimmune diseases and Crohn’s disease (Prochymal, Osiris Therapeutics), cardiac disease (Hearticellgram, Pharmicell), severe limbal stem cell deficiency (Holoclar, Chiesi Farmaceutici), and knee cartilage defects (Caritstem, MEDIPOST). Despite its increasing clinical significance, stem cell therapy for the treatment of malignant tumors has not yet been authorized because previous stem cell therapy required genetic modification of MSC to increase cancer apoptotic ability. Furthermore, the clinical approval of anti‐cancer nanodrugs, such as liposomal and PEGylated drugs, has been extremely limited due to safety issues, including body clearance and materials degradation. Inorganic nanodrugs, such as gold, silica, and carbon‐based nanomaterials, encountered similar safety concerns (i.e., low clearance and nondegradability). For these reasons, the use of nanomaterials requires achieving clinical efficacy with extremely small amounts of nanomaterials (i.e., with low drug concentrations or increased enzymatic activity). However, we need to reevaluate the clinical use of nanomaterials within limited conditions (i.e., ultra‐low concentration) if there is no superior substitute to nanomaterials in terms of drug delivery vehicles. A previous study focused on silica‐nanorattle nanoparticles conjugated on the MSC membrane, which successfully demonstrated membrane‐conjugated nanodrug delivery in the skin‐xenograft mice model.19 However, without a thorough understanding and optimization of nanodrug–MSC conjugation and without success on deep tissue tumor model, such as lung, brain, and pancreas, clinical application will be difficult. In this aspect, covalently conjugated nanodrugs on the membrane of stem cells achieve anti‐cancer efficacy on deep tissue tumor model at ultralow concentrations and, thus, can overcome the side effects associated with toxicity. The dose of the stem cell‐conjugated anti‐cancer nanodrug presented in this study was extremely low (DOX: 0.035 mg kg−1 and CNT: 0.1 mg kg−1), thanks to efficiently coated anti‐cancer nanodrugs on the membrane of MSCs without diminishing the innate functionality of stem cells (i.e., homing ability).

Cell Culture: Human BM‐MSCs (PT‐2501, Lonza) were cultured in MSC medium (MSCBM: PT‐3238, Lonza) with supplements (PT‐4105, Lonza). The human NSCLC cell line H1975 (CRL‐5908, ATCC) was maintained in Roswell Park Memorial Institute 1640 medium (RPMI 1640: 11875‐093, Gibco) supplemented with 10% fetal bovine serum (FBS: 26140, Gibco) and 1% antibiotics (10378016, Gibco). The human NSCLC cell line A549 (CCL‐185, ATCC), human breast cancer cell line MDA‐MB‐231 (HTB‐26, ATCC), human fibroblast cell line NHFB (CC‐2511, Clonetics), and human glioma cell line U87MG (HTB‐14, ATCC) were maintained in high‐glucose Dulbecco’s modified Eagle’s medium (11995‐065, Gibco) supplemented with 10% FBS (16000‐044, Gibco) and 1% antibiotics (10378016, Gibco). Normal lung fibroblast cells, MRC‐5 (CCL‐171, ATCC), were maintained in Eagle’s minimum essential medium (30–2003, ATCC) supplemented with 10% FBS (26140, Gibco) and 1% antibiotics. All cultures were maintained in 5% CO2 at 37 °C.

The authors declare no conflict of interest.

 

Source:

http://doi.org/10.1002/advs.201700860

 

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