Size-adaptable and ligand (biotin)-sheddable nanocarriers equipped with avidin scavenging technology for deep tumor penetration and reduced toxicity.

Abstract

The conventional active-targeting nano-chemotherapy suffers from poor tumor tissue penetration and non-negligible toxicity due to the size/ligand dilemmas and insufficient target selectivity. In this report, a stimuli-responsive size-adaptable and ligand (biotin)-sheddable drug delivery system (DDS) combined with two-step strategy of biotin-avidin system was designed to seek a balance between tumor targeting and penetration as well as to self-scavenge the nonresponsive nanocarriers in normal tissues. This DDS was composed of 'multi-seed' polymeric liposomes (ASL-BIO-MPL) with asulacrine-loaded micelles as seeds in their aqueous cavities. The shell of such liposomes was modified with MMP-9 cleavable polymer-polypeptide functionalized with the tumor targeting ligand biotin. ASL-BIO-MPL could disintegrate into mixture of irregularly-shaped liposomes (~200 nm) and scattered tiny micelles (~40 nm) after incubation with MMP-9. The fluorescence-labeled BIO-MPL could travel to the center of the 4T1 breast tumor spheroids under the action of MMP-9, possibly benefited from the relay of released tiny micelles. Conversely, neither the biotin-modified micelles nor non-MMP-9-responsive multi-seed liposomes could penetrate into the spheroids possibly due to the potent binding-site barrier of biotin and large size, respectively. In tumor-bearing mice, ASL-BIO-MPL exhibited the strongest drug penetrability and thus the optimal inhibition of tumor growth compared to other formulations. Following administration of avidin with a rational dosage regimen, the number of apoptotic cells in normal tissues induced by ASL-BIO-MPL reduced without affecting their targeting effect, suggesting the followed administration of adivin could scavenge the DDS in non-target site. Overall, the size/ligand adapting MPL system combined with two-step strategy of biotin-avidin may provide potential avenues for nanocarriers to enhance deep tumor tissue targeting and protect normal tissues.

• Authors: Ya Jin, Zimei Wu, Chenchen Wu, Yixuan Zi, Xinyu Chu, Jianping Liu, Wenli Zhang
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 320 Pg. 142-158 (04 10 2020) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 31978442 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020. Published by Elsevier B.V.

Chemical References

• Ligands
• Liposomes
• Avidin
• Biotin

Topics

• Animals
• Avidin
• Biotin
• Ligands
• Liposomes
• Mice
• Neoplasms (drug therapy)
• Technology