opportunities and challenges for nanomedicines · zomer &van rheenen lab, hubrecht . 8-12-2015...
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8-12-2015
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Opportunities and Challenges for
Nanomedicines
Ray Schiffelers
Laboratory Clinical Chemistry & Hematology
Vesicles
100 nm
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Passive liposome targeting
Unmodified liposomes are rapidly cleared from the circulation
Depending on size (very small), lipid composition (very rigid), charge (slightly negative) etc.
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Distribution of labeled erythrocytes and
200 nm EPC-liposomes after iv injection
Blood Liposomes
Passive liposome targeting
1978
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Preventing liver and spleen uptake
Coating with poly(ethylene) glycol decelerates liposome uptake by MPS
Blood Liposomes
Distribution of labeled erythrocytes and 100 nm PEG-liposomes after iv injection
Passive liposome targeting
Laverman et al.
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Extravasation through ‘leaky’ inflamed vasculature (EPR effect)
Uchegbu et al. 2008
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Local extravasation
Rheumatoid Arthritis
Crommelin et al, 2002
Kaposi Sarcoma
Harrington et al. 2001
Local extravasation
synovitislung tumor
Harrington et al. 2001
Dams et al. 2000
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Common denominator
Danger
bacteria/tumor cells/antibodies/lipid deposits/messengers
Increased capillary permeability
Influx inflammatory cells/blood
components
Chronic inflammatory
signaling
Vesicles
loading
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Vesicles
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mPEG-DSPEHSPCCholesterol
Doxorubicin-sulphate
Intratumoral concentrations 3-10x increased
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Efficacy in metastatic breast cancer
M. E. R. O’Brien et al. Ann Oncol 2004;15:440-449
Figure 3. Rate of cardiac events versus cumulative anthracycline dose.
M. E. R. O’Brien et al. Ann Oncol 2004;15:440-449
European Society for Medical Oncology
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Hand & Foot syndromeNew DLT
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Extracellulaire vesicles
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Extracellular vesicles
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Zomer &Van Rheenen lab, Hubrecht
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Local transfer
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Conclusion
• EV offers a new angle for RNA delivery
• Exogenous loading is not straightforward
• Cell produced & loaded EV show activity in vivo
• Acceptor cells change phenotype
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