BACKGROUND: Achieving optimal stability of carrier-drug association is key to the effective application of nanomedicines for treating adult and pediatric cancers. Re-engineering drug molecules into reversibly hydrophobized mutual prodrugs [co-drugs] is a new experimental strategy for improving nanocarrier-drug association, while allowing for controlled activation and synchronized release of mutually enhancing co-drug components. In this study, we focused on nanocarrier-based delivery of co-drugs formed with redox-silent tocol derivatives (mitocans) and topoisomerase I inhibitors of the camptothecin family, whose effective clinical use has been compromised by poor stability, incompatibility with conventional delivery vehicles and strong dose-limiting adverse effects. Nanocarrier-mediated delivery of co-drugs is designed to take advantage of enhanced intratumoral retention of sub-100 nm sized nanoparticles [NP], followed by co-drug activation in the tumor tissue. METHODS AND RESULTS: A series of tocol co-drugs with a potent camptothecin analog, SN-38, constructed with progressively increasing activation rates were encapsulated in biodegradable NP [85±36 nm] using a modified nanoprecipitation approach. NP loaded with a phenolic ester co-drug exhibiting the highest activation rate were also found to be most effective against chemo-naïve and chemoresistant neuroblastoma [NB] cells under conditions modeling different levels of NB cell exposure within the tumor. Phenolic carbonate and aliphatic ester designs were notably less efficient. In an in vivo model of previously untreated disease, nanocarriers with phenolic ester co-drug administered over 4 weeks [10 mg/kg, once a week] induced tumor regression and completely inhibited tumor growth over a 26-week period. The same co-drug/nanocarrier formulation tested against chemoresistant NB potently suppressed tumor growth and extended animal survival up to 7 weeks, in contrast to a marginal and transient effect of the clinically used SN-38 precursor, irinotecan [event-free survival of 3 weeks vs. 2 weeks in ‘no treatment’ and drug-free NP groups]. CONCLUSIONS: Camptothecin-mitocan co-drugs can be rationally designed as therapeutic cargoes for nanocarrier-based cancer therapy. The co-drug/nanocarrier combination strategy, whose feasibility and effectiveness against high-risk NB was demonstrated in the present preclinical studies, holds promise as a treatment for aggressive pediatric and adult solid tumors.

Mutual prodrugs for treating aggressive neuroblastoma with biodegradable nanocarriers

256th National Meeting (2018)

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