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Published on: December 15, 2010
Sonopermeation With Size-sorted Microbubbles Synergistically Increases Survival and Enhances Tumor Apoptosis With
Rachael M Sundland1, Donia Ballan1, Kylie M Callier1
1Department of Surgery, Section of Pediatric Surgery, The University of Chicago Medicine.
Objective:
Despite aggressive therapy, approximately 50% of patients with neuroblastoma (NB) fail to respond, and survivors endure lifelong toxicities. Sonopermeation increases drug uptake via cell bilayer disruption through focused ultrasound and microbubbles (MBs)-gas-filled, sound sensitive lipid spheres. MB response to a given ultrasound pulse (cavitation) varies according to MB size. We asked whether size-sorted MBs (SSMB) 4 to 5 µm in diameter will more consistently and predictably enhance doxorubicin uptake, compared with polydisperse MBs (PMB, 0.5-10 µm in diameter), thereby increasing drug delivery to NB xenografts.
Methods:
Human NB cells were implanted into the left kidney of nude mice and grown for 5 to 6 wk. Mice received sonopermeation alongside either PMB or SSMB at low (0.6 MPa) or high (2 MPa) negative pressures. Some mice also received different chemotherapy agents (doxorubicin, etoposide or cyclophosphamide). Circulating tumor cells were assessed by flow cytometry 1 h after treatment. Survival was assessed for up to 21 d, a subset of mice was euthanized 24 h after treatment for histological assessment of apoptosis, vascular lumen size and tight junctions.
Results:
Tumors treated with SSMB and high pressure showed synergy with liposomal doxorubicin (L-DOX) owing to increased vascular lumen and disruption of tight junctions, resulting in drug uptake, apoptosis, lack of tumor growth and increased survival. We found no difference in the numbers of circulating tumor cells.
Conclusion:
Sonopermeation with SSMB at 2 MPa synergizes with L-DOX delivery, increasing apoptosis, perfusion and vascular permeability, suggesting that SSMB sonopermeation at high pressure is promising for NB-targeted treatment, especially in combination with L-DOX.
Insights
Size-sorted microbubbles (SSMB) combined with high-pressure sonopermeation enhance doxorubicin delivery for neuroblastoma treatment, improving drug uptake and survival rates.
Area of Science:
- Oncology
- Biomedical Engineering
- Nanotechnology
Background:
- Neuroblastoma (NB) treatment faces challenges with drug resistance and toxicities.
- Sonopermeation, using focused ultrasound and microbubbles (MBs), enhances drug delivery by disrupting cell bilayers.
- Microbubble response to ultrasound depends on their size, influencing treatment efficacy.
Purpose of the Study:
- To evaluate if size-sorted microbubbles (SSMB) improve doxorubicin delivery to neuroblastoma xenografts compared to polydisperse microbubbles (PMB).
- To assess the impact of SSMB sonopermeation at different pressures on drug uptake and therapeutic outcomes in neuroblastoma.
Main Methods:
- Neuroblastoma xenografts were established in nude mice.
- Sonopermeation was performed using either PMB or SSMB at low (0.6 MPa) or high (2 MPa) pressures, with doxorubicin or other chemotherapy agents.
- Tumor response, circulating tumor cells, apoptosis, vascular lumen size, and tight junction integrity were assessed.
Main Results:
- SSMB sonopermeation at high pressure (2 MPa) demonstrated synergy with liposomal doxorubicin (L-DOX).
- This combination led to increased vascular lumen, disrupted tight junctions, enhanced drug uptake, significant apoptosis, inhibited tumor growth, and improved survival.
- No significant difference was observed in circulating tumor cell counts.
Conclusions:
- Sonopermeation with SSMB at high pressure effectively synergizes with L-DOX for neuroblastoma treatment.
- The approach enhances apoptosis, perfusion, and vascular permeability, showing promise for targeted NB therapy.
- SSMB sonopermeation at high pressure is a promising strategy for improving neuroblastoma treatment outcomes, particularly when combined with L-DOX.
