Poly(2-oxazoline) nanoparticle delivery enhances the therapeutic potential of vismodegib for medulloblastoma by improving CNS pharmacokinetics and reducing systemic toxicity

Drug Delivery Systems for Hedgehog Inhibitors in the Treatment of SHH-Medulloblastoma

“…Moreover, POxvismo showed a limited toxicity effect on bone growth compared to free vismodegib in C57BL/6 mice treated at several post-natal days. Although, POx-vismo exhibited similar pharmacodynamic effects to systemically administer free vismodegib, this drug delivery system resulted to be more efficient to prolong survival in MBprone G-Smo mice, with 30% of mice surviving to 35 days compared to the control group (Hwang et al, 2020). These evidences underline as SMO antagonists encapsulated in NPs drug delivery system for the treatment of SHH-MB, could improve their ability to target the specific tumor site at optimal therapeutic concentration, thus mitigating their toxic effects.…”

“…Vismodegib is able to bind the TMD of SMO and to induce tumor regression in a Ptch +/derived MB allograft mouse model (Robarge et al, 2009). Hwang et al (2020) used the thin film method to generate micelles with vismodegib:POx polymer (POx-vismo) in different ratios (2:10, 4:10, 6:10, and 8:10 w/w) (Hwang et al, 2020). The loading efficiency of vismodegib encapsulated in POx was nearly 90% and the loading capacity ranking from 13.5 to 42.4% w/w, depending on the drug:polymer ratio (Hwang et al, 2020).…”

“…Moreover, POx-vismo showed a limited toxicity effect on bone growth compared to free vismodegib in C57BL/6 mice treated at several post-natal days. Although, POx-vismo exhibited similar pharmacodynamic effects to systemically administer free vismodegib, this drug delivery system resulted to be more efficient to prolong survival in MB-prone G-Smo mice, with 30% of mice surviving to 35 days compared to the control group ( Hwang et al, 2020 ).…”

“…A valid candidate in generating nanoparticle-based therapeutic products for tumor treatment is represented by the poly(2-oxazoline) amphiphilic block copolymer (POx). This drug delivery system, used for ovarian, breast, and lung cancers, has recently been described to optimize the clinical features of vismodegib (2-chloro- N -(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide), the first FDA-approved inhibitor of SMO with low aqueous solubility and reduced bioavailability ( Table 1 ; Figure 1 ) ( Luxenhofer et al, 2010 ; Han et al, 2012 ; Hwang et al, 2020 ). Vismodegib is a benzamide obtained by formal condensation between the carboxy group of 2-chloro-4-(methylsulfonyl)benzoic acid and the anilino group of 4-chloro-3-(pyridin-2-yl).…”

“…The analysis of exposure of tissues to the drug over time showed for the POx-vismo an improved uptake across BBB and limited distribution to nontarget organs, compared to free vismodegib. Similarly, the administration of POx-vismo in C57BL/6 mice with intact BBB increased CNS penetration, thus reducing systemic biodistribution ( Hwang et al, 2020 ). Moreover, POx-vismo showed a limited toxicity effect on bone growth compared to free vismodegib in C57BL/6 mice treated at several post-natal days.…”