opportunities and challenges for nanomedicines · zomer &van rheenen lab, hubrecht . 8-12-2015...

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8-12-2015 1 Opportunities and Challenges for Nanomedicines Ray Schiffelers Laboratory Clinical Chemistry & Hematology Vesicles 100 nm

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Page 1: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

8-12-2015

1

Opportunities and Challenges for

Nanomedicines

Ray Schiffelers

Laboratory Clinical Chemistry & Hematology

Vesicles

100 nm

Page 2: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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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.

Page 3: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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Distribution of labeled erythrocytes and

200 nm EPC-liposomes after iv injection

Blood Liposomes

Passive liposome targeting

1978

Page 4: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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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.

Page 5: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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Extravasation through ‘leaky’ inflamed vasculature (EPR effect)

Uchegbu et al. 2008

Page 6: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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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

Page 7: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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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

Page 8: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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Vesicles

Page 9: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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mPEG-DSPEHSPCCholesterol

Doxorubicin-sulphate

Intratumoral concentrations 3-10x increased

Page 10: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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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

Page 11: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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Hand & Foot syndromeNew DLT

Page 12: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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Page 13: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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Extracellulaire vesicles

Page 14: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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Extracellular vesicles

Page 15: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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Zomer &Van Rheenen lab, Hubrecht

Page 16: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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Page 17: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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Local transfer

Page 18: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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Page 19: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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Page 20: Opportunities and Challenges for Nanomedicines · Zomer &Van Rheenen lab, Hubrecht . 8-12-2015 16. 8-12-2015 17 Local transfer. 8-12-2015 18. 8-12-2015 19. 8-12-2015 20 Conclusion

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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