Targeted microbubbles carrying lipid-oil-nanodroplets for ultrasound-triggered delivery of the hydrophobic drug, combretastatin A4

• Published in: Nanomedicine Vol. 36; p. 102401
• Main Authors: Charalambous, Antonia, Mico, Victoria, McVeigh, Laura E., Marston, Gemma, Ingram, Nicola, Volpato, Milène, Peyman, Sally A., McLaughlan, James R., Wierzbicki, Antonia, Loadman, Paul M., Bushby, Richard J., Markham, Alexander F., Evans, Stephen D., Coletta, P. Louise
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2021
• Subjects: Animals; Cell Line, Tumor; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Combretastatin A4; Humans; Hydrophobic and Hydrophilic Interactions; Lipid-Oil-Nanodroplets (LONDs); Lipids - chemistry; Lipids - pharmacokinetics; Lipids - pharmacology; Mice; Mice, Inbred BALB C; Mice, Nude; Microbubbles; Nanostructures - chemistry; Nanostructures - therapeutic use; Stilbenes - chemistry; Stilbenes - pharmacokinetics; Stilbenes - pharmacology; Targeting; Ultrasonography; Ultrasound trigger; Xenograft Model Antitumor Assays; LOD; VEGFR2; Combretastatin A4; Targeting; Tx; CA4P; EPR; Ultrasound trigger; i.p; ICAM-1; CA4G; LONDs; i.v; Lipid-Oil-Nanodroplets (LONDs); VDA; CRC; CA4; TGI; Microbubbles; CEPs; US; 5-FU; MBs
• DOI: 10.1016/j.nano.2021.102401
• ISSN: 1549-9634

The hydrophobicity of a drug can be a major challenge in its development and prevents the clinical translation of highly potent anti-cancer agents. We have used a lipid-based nanoemulsion termed Lipid-Oil-Nanodroplets (LONDs) for the encapsulation and in vivo delivery of the poorly bioavailable combretastatin A4 (CA4). Drug delivery with CA4 LONDs was assessed in a xenograft model of colorectal cancer. LC–MS/MS analysis revealed that CA4 LONDs, administered at a drug dose four times lower than drug control, achieved equivalent concentrations of CA4 intratumorally. We then attached CA4 LONDs to microbubbles (MBs) and targeted this construct to VEGFR2. A reduction in tumor perfusion was observed in CA4 LONDs-MBs treated tumors. A combination study with irinotecan demonstrated a greater reduction in tumor growth and perfusion (P = 0.01) compared to irinotecan alone. This study suggests that LONDs, either alone or attached to targeted MBs, have the potential to significantly enhance tumor-specific hydrophobic drug delivery. A number of highly potent and promising drugs fail to reach the clinic due to poor-water solubility. Lipid-stabilized Oil Nanodroplets (LONDs) were produced specifically for the encapsulation of poorly-water soluble drugs such as the vascular disruptive agent Combretastatin A4 (CA4). Initial pre-clinical work with CA4 LONDs showed an accumulation of CA4 in tumor tissue. Attachment of CA4 LONDs to VEGFR2-targeted Microbubbles (MBs) permitted the controlled and ultrasound triggered release of CA4 in tumors, confirmed by a reduction in tumor perfusion post-treatment. The combination of low dose irinotecan with CA4 LONDs-MBs further enhanced the anti-tumor effects of both compounds [Display omitted]