peptide-loaded exosomes from mature DC with IFNc stimulation was tested as
maintenance immunotherapy after the first line chemotherapy in 22 patients with
advanced NSCLC, which have shown that DC exosomes with IFNc activated
antitumor immunity [45]. Meanwhile, tumor-driven exosomes also have been
considered for tumor antigen source for immune-stimulation [46]. However, given
that tumor exosomes inherently induce immune suppressive effect via delivery of
immunomodulatory factor [47], administration of native tumor exosome for tumor
treatment was not sufficient for immune stimulatory anti-tumor therapy [48]. To
overcome the immune suppressive effect of tumor-derived exosomes, a combination of tumor exosomes with immune stimulatory adjuvant treatment had been
developed and successfully improved the anti-tumor response of immune effector
cells [49]. A phase I clinical trial proved the feasibility and safety of tumor-derived
exosomes for anti-tumor immunotherapy [50]. In addition, exosomes derived from
human NK cells were also shown to stimulate the anti-tumor immune response
in vitro [51].
9.3.2 Targeted Drug Delivery
There have been many studies to develop and validate various drug delivery systems in different types of cancer [52, 53]. Encapsulating anticancer drugs within
synthetic biomaterials such as liposomes showed advantages of increased efficacy,
biocompatibility, and reduced toxicity, but it also had disadvantages of immunogenicity, low solubility, short half-life, and high cost [54]. Toxicity of synthetic
biomaterials was associated even with synthetic biomaterials themselves, i.e.,
micelles, and liposomes [55]. Recently, exosomes emerged as a new drug-delivery
system with inherent advantages of natural targeting property, less toxicity, less
immunogenicity, and highly efficient internalization by target cells compared to
synthetic liposomes of extrinsic drug cargos [56]. However, the problems of exosomes like low yield, low solubility, non-specific targeting, and short half-life in the
circulation should be overcome to use exosomes practically as drug-delivery
vehicle in clinical situation.
Exosomes are released only in small amounts from mammalian cells, and thus
harvesting exosomes which were naturally released from cells are generally
cost-ineffective and time-consuming, which results in a low yield [57].
Exosome-mimetic nanovesicles which were produced by serial extrusion through
diminishing pore-sized filters (10, 5, 1 lm) was suggested to obtain a higher yield
of nanovesicles [58]. The doxorubicin loaded exosome-mimetic nanovesicles
obtained from U937 human monocytes or Raw 264.7 murine macrophages showed
100-fold higher production yield and similar in vivo antitumor effect compared to
those of the doxorubicin loaded exosomes. The exosome-mimetic vesicles inherit
the character of monocytes or macrophages, which recognize endothelial cell
adhesion molecules (CAM) for extravasation. Tumors grow rapidly with abnormal
angiogenesis, therefore rapidly growing endothelial cells expressing CAMs is a
9 Endogenous Radionanomedicine: Validation of Therapeutic Potential
175
maintenance immunotherapy after the first line chemotherapy in 22 patients with
advanced NSCLC, which have shown that DC exosomes with IFNc activated
antitumor immunity [45]. Meanwhile, tumor-driven exosomes also have been
considered for tumor antigen source for immune-stimulation [46]. However, given
that tumor exosomes inherently induce immune suppressive effect via delivery of
immunomodulatory factor [47], administration of native tumor exosome for tumor
treatment was not sufficient for immune stimulatory anti-tumor therapy [48]. To
overcome the immune suppressive effect of tumor-derived exosomes, a combination of tumor exosomes with immune stimulatory adjuvant treatment had been
developed and successfully improved the anti-tumor response of immune effector
cells [49]. A phase I clinical trial proved the feasibility and safety of tumor-derived
exosomes for anti-tumor immunotherapy [50]. In addition, exosomes derived from
human NK cells were also shown to stimulate the anti-tumor immune response
in vitro [51].
9.3.2 Targeted Drug Delivery
There have been many studies to develop and validate various drug delivery systems in different types of cancer [52, 53]. Encapsulating anticancer drugs within
synthetic biomaterials such as liposomes showed advantages of increased efficacy,
biocompatibility, and reduced toxicity, but it also had disadvantages of immunogenicity, low solubility, short half-life, and high cost [54]. Toxicity of synthetic
biomaterials was associated even with synthetic biomaterials themselves, i.e.,
micelles, and liposomes [55]. Recently, exosomes emerged as a new drug-delivery
system with inherent advantages of natural targeting property, less toxicity, less
immunogenicity, and highly efficient internalization by target cells compared to
synthetic liposomes of extrinsic drug cargos [56]. However, the problems of exosomes like low yield, low solubility, non-specific targeting, and short half-life in the
circulation should be overcome to use exosomes practically as drug-delivery
vehicle in clinical situation.
Exosomes are released only in small amounts from mammalian cells, and thus
harvesting exosomes which were naturally released from cells are generally
cost-ineffective and time-consuming, which results in a low yield [57].
Exosome-mimetic nanovesicles which were produced by serial extrusion through
diminishing pore-sized filters (10, 5, 1 lm) was suggested to obtain a higher yield
of nanovesicles [58]. The doxorubicin loaded exosome-mimetic nanovesicles
obtained from U937 human monocytes or Raw 264.7 murine macrophages showed
100-fold higher production yield and similar in vivo antitumor effect compared to
those of the doxorubicin loaded exosomes. The exosome-mimetic vesicles inherit
the character of monocytes or macrophages, which recognize endothelial cell
adhesion molecules (CAM) for extravasation. Tumors grow rapidly with abnormal
angiogenesis, therefore rapidly growing endothelial cells expressing CAMs is a
9 Endogenous Radionanomedicine: Validation of Therapeutic Potential
175