Stabilized phospholipid-topotecan prodrug particles increase vascular permeability and ultrasound-enhanced neuroblastoma delivery.

Authors

Mendi Marquez, Fernando Flores-Guzman, Isabella Iwanicki, Lydia Wu, Jacky Villa-Gomez, Paula Viza-Gomes, Rachael Sundland, Mohammadaref Ghaderi, Liliya V Frolova, Shashank R Sirsi, Michaelann Tartis, Sonia L Hernandez

Published in

International journal of pharmaceutics. Pages 127283. Aug 06, 2026. Epub Aug 06, 2026.

Abstract

Neuroblastoma (NB) accounts for 15% of pediatric cancer deaths, with high-risk patients having < 50% 5-year survival despite intensive treatment. Topotecan (TPT), a topoisomerase I inhibitor in standard therapy, has limited efficacy due to its short plasma half-life of 30 min. We synthesized a phospholipid-topotecan prodrug (2 T-T) and incorporated it into liposomes (L-2TT) to enhance drug loading and delivery. We hypothesized L-2TT would demonstrate superior efficacy versus free topotecan, with further controlled release when combined with sonopermeation (microbubble cavitation driven by spatially targeted ultrasound). We evaluated L-2TT in in vitro and in vivo models. L-2TT showed nearly 3-fold lower IC₅₀ values than topotecan-HCl in 7 of 8 NB cell lines, with preferential uptake in NB versus K562 leukemia cells. L-2TT was well-tolerated in vivo with dyed liposome circulation evident with IVIS imaging for 48 h. In nude mice with intrarenal xenografts, L-2TT induced 3-fold higher tumor apoptosis than topotecan-HCl (p < 0.0001), which exceeded controls by 3-fold (p < 0.001). L-2TT also enhanced perivascular apoptosis, increased vascular permeability and reduced tumor hypoxia (7 of 8 L-2TT-treated versus 1 of 9 control tumors, p < 0.05). RNA-seq revealed downregulation of chemoresistance associated transporters (ABCA1) compared to TPT. Sonopermeation doubled L-2TT-induced apoptotic area (p < 0.05). The liposomal topotecan prodrug L-2TT demonstrates superior potency versus free topotecan through enhanced pharmacokinetic stability and tumor vascular permeability, where sonopermeation further augments efficacy. This dual-modality approach combining controlled release with ultrasound-mediated delivery offers a promising therapeutic strategy for high-risk neuroblastoma treatment.

PMID:
42562131
Bibliographic data and abstract were imported from PubMed on 07 Aug 2026.

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