Investigation of the Antitumor Activity and Toxicity of Tumor-Derived Exosomes Fused with Long-Circulating and pH-Sensitive Liposomes Containing Doxorubicin

Abstract

Exosome–liposome hybrid nanocarriers containing chemotherapeutic agents have been developed to enhance drug delivery, improve the efficacy of the treatment of metastatic cancer, and overcome chemoresistance in cancer therapy. Thus, the objectives of this study were to investigate the toxicological profiles of exosomes fused with long-circulating and pH-sensitive liposomes containing doxorubicin (ExoSpHL-DOX) in healthy mice and the antitumor activity of ExoSpHL-DOX in Balb/c female mice bearing 4T1 breast tumors. The acute toxicity was determined by evaluating the mortality and morbidity of the animals and conducting hematological, biochemical, and histopathological analyses after a single intravenous administration of ExoSpHL-DOX. The results of the study indicated that the ExoSpHL-DOX treatment is less toxic than the free doxorubicin (DOX) treatment. ExoSpHL-DOX showed no signs of nephrotoxicity, even at the highest dose of DOX, indicating that the hybrid nanosystem may alter the distribution of DOX and reduce the kidney damage. Regarding the antitumor activity, ExoSpHL-DOX showed an antitumor effect compared to the control group. Furthermore, the hybrid nanocarrier of tumor-derived exosomes fused with long-circulating and pH-sensitive liposomes reduced the number of metastatic foci in the lungs. These results indicate that ExoSpHL-DOX may be a promising nanocarrier for the treatment of breast cancer, reducing toxicity and inhibiting metastasis, mainly in the lungs.

Exosomes: Diagnostic and Therapeutic Implications in Cancer

“…For example, the limited yield of exosomes could not satisfy the therapeutic application requirements in preclinical and clinical studies. Hybrid exosomes containing liposomes may increase exosome yield [ 134 ]. Naive exosomes show fast clearance, hepatic accumulations, and a lack of target-specific tropism.…”

“…This method can improve drug loading efficacy while maintaining the functions of exosomes. These hybrid exosomes can be endocytosed by MSCs and subsequently release their cargo [ 134 ]. Future studies should aim to reduce any unnecessary immune reactions caused by these exosomes containing miRNAs.…”

“…Methods for loading these cargoes include electroporation, sonication, co-incubation, and extrusion [ 136 , 137 , 138 , 139 , 140 , 141 ]. Endogenous loading involves the packaging of biomolecules via the modification of donor cells [ 133 , 134 , 142 , 143 , 144 , 145 ]. This modification of donor cells can be performed by means of the transfection of DNAs and various ncRNAs.…”

Research Advances of Engineered Exosomes as Drug Delivery Carrier

“…Hybridization increases the size of exosomes and helps to improve drug loading efficiency and facilitate loading of macromolecular cargos. Gomes et al fused long-circulating and pH-sensitive liposomes containing DOX to breast cancer tumor-derived exosomes for the treatment of breast cancer, with 88.5% DOX encapsulation, lower toxicity, and higher antitumor effect . The disadvantage of membrane fusion is that it changes the integrity and orientation of exosomal membrane proteins, which may weaken the biological function of exosomes.…”

“…Gomes et al fused long-circulating and pH-sensitive liposomes containing DOX to breast cancer tumor-derived exosomes for the treatment of breast cancer, with 88.5% DOX encapsulation, lower toxicity, and higher antitumor effect. 94 The disadvantage of membrane fusion is that it changes the integrity and orientation of exosomal membrane proteins, which may weaken the biological function of exosomes. Physical modifications, in addition to membrane fusion, can also involve incorporating lipid components or cell membrane staining dyes with lipophilicity/hydrophobicity into the exosomal membrane as anchors.…”