Safe and Effective Delivery of Antitumor Drug Using Mesenchymal Stem Cells Impregnated with Submicron Carriers

An important area in modern malignant tumor therapy is the optimization of antitumor drugs pharmacokinetics. The use of some antitumor drugs is limited in clinical practice due to their high toxicity. Therefore, the strategy for optimizing the drug pharmacokinetics focuses on the generation of high...

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Bibliographic Details
Published in:ACS applied materials & interfaces 2019-04, Vol.11 (14), p.13091-13104
Main Authors: Timin, Alexander S, Peltek, Oleksii O, Zyuzin, Mikhail V, Muslimov, Albert R, Karpov, Timofey E, Epifanovskaya, Olga S, Shakirova, Alena I, Zhukov, Mikhail V, Tarakanchikova, Yana V, Lepik, Kirill V, Sergeev, Vladislav S, Sukhorukov, Gleb B, Afanasyev, Boris V
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Adhesion - drug effects
Cell Line, Tumor
Cell Movement - drug effects
Cell Proliferation - drug effects
Chemokine CXCL12 - genetics
Collagen - chemistry
Collagen - pharmacology
Drug Carriers - chemistry
Drug Carriers - pharmacology
Drug Delivery Systems
Gene Expression Regulation, Neoplastic - drug effects
Humans
Mesenchymal Stem Cells - chemistry
Neoplasm Invasiveness - genetics
Neoplasm Invasiveness - pathology
Neoplasms - drug therapy
Neoplasms - pathology
Primary Cell Culture
Receptors, CXCR4 - genetics
Signal Transduction - drug effects
Spheroids, Cellular - drug effects
Vincristine - chemistry
Vincristine - pharmacology
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Summary:An important area in modern malignant tumor therapy is the optimization of antitumor drugs pharmacokinetics. The use of some antitumor drugs is limited in clinical practice due to their high toxicity. Therefore, the strategy for optimizing the drug pharmacokinetics focuses on the generation of high local concentrations of these drugs in the tumor area with minimal systemic and tissue-specific toxicity. This can be achieved by encapsulation of highly toxic antitumor drug (vincristine (VCR) that is 20–50 times more toxic than widely used the antitumor drug doxorubicin) into nano- and microcarriers with their further association into therapeutically relevant cells that possess the ability to migrate to sites of tumor. Here, we fundamentally examine the effect of drug carrier size on the behavior of human mesenchymal stem cells (hMSCs), including internalization efficiency, cytotoxicity, cell movement, to optimize the conditions for the development of carrier-hMSCs drug delivery platform. Using the malignant tumors derived from patients, we evaluated the capability of hMSCs associated with VCR-loaded carriers to target tumors using a three-dimensional spheroid model in collagen gel. Compared to free VCR, the developed hMSC-based drug delivery platform showed enhanced antitumor activity regarding those tumors that express CXCL12 (stromal cell-derived factor-1 (SDF-1)) gene, inducing directed migration of hMSCs via CXCL12 (SDF-1)/CXCR4 pathway. These results show that the combination of encapsulated antitumor drugs and hMSCs, which possess the properties of active migration into tumors, is therapeutically beneficial and demonstrated high efficiency and low systematic toxicity, revealing novel strategies for chemotherapy in the future.
ISSN:1944-8244
1944-8252
DOI:10.1021/acsami.8b22685