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Engineered Cell-Derived Vesicles Displaying Targeting Peptide and Functionalized with Nanocarriers for Therapeutic microRNA Delivery to Triple-Negative Breast Cancer in Mice.

Rajendran Jc BoseUday Sukumar KumarFernando Garcia-MarquesYitian ZengFrezghi HabteJason R McCarthySharon PitteriTarik F MassoudRamasamy Paulmurugan
Published in: Advanced healthcare materials (2021)
Polymeric nanocarriers (PNCs) can be used to deliver therapeutic microRNAs (miRNAs) to solid cancers. However, the ability of these nanocarriers to specifically target tumors remains a challenge. Alternatively, extracellular vesicles (EVs) derived from tumor cells show homotypic affinity to parent cells, but loading sufficient amounts of miRNAs into EVs is difficult. Here, we investigate whether uPAR-targeted delivery of nanococktails containing PNCs loaded with therapeutic antimiRNAs, and coated with uPA engineered extracellular vesicles (uPA-eEVs) can elicit synergistic antitumor responses. The uPA-eEVs coating on PNCs increases natural tumor targeting affinities, thereby enhancing the antitumor activity of antimiRNA nanococktails. The systemic administration of uPA-eEV-PNCs nanococktail showed a robust tumor tropism, which significantly enhanced the combinational antitumor effects of antimiRNA-21 and antimiRNA-10b, and led to significant tumor regression and extension of progression free survival for syngeneic 4T1 tumor-bearing mice. In addition, the uPA-eEV-PNCs-antimiRNAs nanococktail plus low dose doxorubicin resulted in a synergistic antitumor effect as evidenced by inhibition of tumor growth, reduction of lung metastases, and extension of survival of 4T1 tumor-bearing mice. Our targeted combinational nanococktail strategy could be readily translated to the clinical setting by using autologous cancer cells that have flexibility for ex vivo expansion and genetic engineering. This article is protected by copyright. All rights reserved.
Keyphrases
  • cancer therapy
  • drug delivery
  • low dose
  • stem cells
  • induced apoptosis
  • type diabetes
  • bone marrow
  • cell death
  • mesenchymal stem cells
  • oxidative stress
  • young adults
  • genome wide