Modified Bovine Milk Exosomes for Doxorubicin Delivery to Triple-Negative Breast Cancer Cells

Abstract

Biological nanoparticles, such as exosomes, offer an approach to drug delivery because of their innate ability to transport biomolecules. Exosomes are derived from cells and an integral component of cellular communication. However, the cellular cargo of human exosomes could negatively impact their use as a safe drug carrier. Additionally, exosomes have the intrinsic yet enigmatic, targeting characteristics of complex cellular communication. Hence, harnessing the natural transport abilities of exosomes for drug delivery requires predictably targeting these biological nanoparticles. This manuscript describes the use of two chemical modifications, incorporating a neuropilin receptor agonist peptide (iRGD) and a hypoxia-responsive lipid for targeting and release of an encapsulated drug from bovine milk exosomes to triple-negative breast cancer cells. Triple-negative breast cancer is a very aggressive and deadly form of malignancy with limited treatment options. Incorporation of both the iRGD peptide and hypoxia-responsive lipid into the lipid bilayer of bovine milk exosomes and encapsulation of the anticancer drug, doxorubicin, created the peptide targeted, hypoxia-responsive bovine milk exosomes, iDHRX. Initial studies confirmed the presence of iRGD peptide and the exosomes’ ability to target the αvβ3 integrin, overexpressed on triple-negative breast cancer cells’ surface. These modified exosomes were stable under normoxic conditions but fragmented in the reducing microenvironment created by 10 mM glutathione. In vitro cellular internalization studies in monolayer and three-dimensional (3D) spheroids of triple-negative breast cancer cells confirmed the cell-killing ability of iDHRX. Cell viability of 50% was reached at 10 μM iDHRX in the 3D spheroid models using four different triple-negative breast cancer cell lines. Overall, the tumor penetrating, hypoxia-responsive exosomes encapsulating doxorubicin would be effective in reducing triple-negative breast cancer cells’ survival.

Clinical Impact of Exosomes in Colorectal Cancer Metastasis

“…The therapeutic expectation from surgery, radiotherapy, and chemotherapy for CRC is not so much significant and has multiple complications after treatment. Therapeutic approach based on exosomes is very efficient in cancer treatment. ,− High chemo exposure and CRC-derived exosomes miRNA-24 lead to the development of chemoresistance and stem cells of cancer cells. , Colon cancer stem cells (CSCs) are responsible for cancer recurrence even after treatment. However, it has also been shown that survivability can be improved by targeted therapy to eradicate CSCs .…”

Extracellular Vesicles in Breast Cancer: From Biology and Function to Clinical Diagnosis and Therapeutic Management

“…Many kinds of SEV-based therapies have been shown to improve chemotherapy effectiveness. SEVs have been used to deliver chemotherapeutic drugs such as paclitaxel (PTX) [ 556 , 557 , 558 ] or doxycycline (DOX) [ 559 , 560 , 561 ]. While loading DOX in SEVs reduces its cardiotoxicity [ 562 , 563 ], it also enhances its efficacy when compared to traditional administration [ 562 , 564 ].…”

Extracellular Vesicles from Animal Milk: Great Potentialities and Critical Issues

“…Doxorubicin-loaded-mEV target therapy was previously tested through the induction of hyaluronan expression onto the phospholipid bilayer that is a ligand for the CD44 receptor, thus allowing for CD44-overexpressing, cell-specific drug delivery [ 226 ]. Indeed, mEVs have been evaluated for drug loading and its effects in several molecules and pathologies, especially cancer, with promising and encouraging results in terms of efficacy and safety; the drug power was amplified but the side effects were reduced by the action of the mEVs being more targeted [ 227 , 228 , 229 , 230 , 231 ].…”