Nanoparticle delivery of an SN38 conjugate is more effective than irinotecan in a mouse model of neuroblastoma

Abstract

Neuroblastoma (NB) is the most common and deadly solid tumor in children. The majority of NB patients have advanced stage disease with poor prognosis, so more effective, less toxic therapy is needed. We developed a novel nanocarrier-based strategy for tumor-targeted delivery of a prodrug of SN38, the active metabolite of irinotecan. We formulated ultrasmall-sized ( < 100 nm) biodegradable poly(lactide)-poly(ethylene glycol) based nanoparticles (NPs) containing SN38 conjugated to tocopherol succinate (SN38-TS). Alternative dosing schedules of SN38-TS NPs were compared to irinotecan. Comparison of SN38-TS NPs (2 doses) with irinotecan (20 doses) showed equivalent efficacy but no cures. Comparison of SN38-TS NPs (8, 8, and 16 doses, respectively) to irinotecan (40 doses) showed that all SN38-TS NP regimens were far superior to irinotecan, and “cures” were obtained in all NP arms. SN38-TS NP delivery resulted in 200x the amount of SN38 in NB tumors at 4 hr post-treatment, compared to SN38 detected for the irinotecan arm; no toxicity was seen with NPs. We conclude that this SN38-TS NP formulation improved delivery, retention, and efficacy, without causing systemic toxicity.

Targeted drug distribution in tumor extracellular fluid of GD2-expressing neuroblastoma patient-derived xenografts using SN-38-loaded nanoparticles conjugated to the monoclonal antibody 3F8

“…Our results in the GD2-low PDX model, showing similar activity of GD2-targeted NPs and control NPs, suggest that active targeting with 3F8-NPs was likely to be more critical than the EPR effect to achieve prolonged drug exposure in our neuroblastoma PDX models. Other authors have shown that tocopherol succinate-conjugated SN-38, loaded in non targeted PLA-PEG NPs (<100 nm), improved the activity of systemic irinotecan in neuroblastoma xenografts and accumulated in tumors due to the EPR effect [12]. …”

“…Similarly, novel formulations of SN-38 prodrugs designed for intravenous (i.v.) administration showed higher efficacy in neuroblastoma xenografts [12, 13]. In other cancers, SN-38-loaded self-assembly nanoparticles (NPs) have consistently outperformed irinotecan [14].…”

Preparation and Characterization of SN-38-Encapsulated Phytantriol Cubosomes Containing α-Monoglyceride Additives

“…Nanoparticles have been used to encapsulate a wide variety of poorly water-soluble drugs, leading to dramatic improvements in their solubility, stability and drug-targeting properties, as well as reducing any adverse effects. [10][11][12][13] Furthermore, nanoparticles-based drug delivery systems can preferentially target tumors by taking advantage of the enhanced permeability and retention (EPR) effect. 14) A broad range of drug delivery systems, including PEGylated conjugates, polymer micelles, liposome formulations and dendrimers, have been extensively investigated for the formulation of SN-38 to improve its water solubility and bioavailability.…”

Co-delivery of paclitaxel and TOS-cisplatin via TAT-targeted solid lipid nanoparticles with synergistic antitumor activity against cervical cancer

“…This compound has been found to inhibit the proliferation of various cancer cells in vitro and in vivo, [20][21][22][23][24][25][26] including cervical cancer cells, breast cancer cells, prostate cancer cells, gastric cancer cells, and so on. TOS, a mitochondria-targeting drug, has the synergic effect on nuclear DNA-damaging drugs such as CDDP.…”