Treatment of high-risk neuroblastoma remains one of the greatest challenges for pediatric oncologists. Vincristine (VCR) is effective for the treatment of neuroblastoma. The clinical efficacy of VCR is limited, however, due to its neurotoxic effect, unfavorable pharmacokinetics, and poor drug exposure and delivery to target tissues. Marqibo(r) is the first liposomal formulation of VCR that could improve the pharmacokinetics and toxicity profiles of VCR. However, the lack of pegylation and relatively large size (~150 nm) of Marqibo(r) may result in unfavorable biodistribution and less deeper tumor penetration. Marqibo(r) is only used in clinic to treat adults with a very rare type of leukemia called Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL). The safety and effectiveness of Marqibo(r) in pediatric patients have not been established. It has been reported that smaller nanoparticles such as 30 nm micelles could penetrate poorly permeable tumors for a better anti-tumor effect. The smart VCR loaded micellar nanoparticles (nano-VCR) with smaller size (~16 nm) and on-demand drug releasing properties to be developed in this proposal may offer better efficacy and toxicity profile against neuroblastoma, therefore have great commercial potentials to lead to a marketable VCR-nanoformulation for the treatment of neuroblastoma. The overall goal of this Phase I SBIR proposal is to develop highly effective and less toxic micellar formulation of VCR against neuroblastoma in preclinical animal models, providing validation regarding the feasibility for Phase II studies that will eventually lead to an IND filing to FDA. Our hypotheses are: (i) The smaller crosslinked micelle formulation of VCR (nano-VCR), compared to its free form are more efficacious and less toxic against neuroblastoma; (ii) Fine tuning the level of disulfide crosslinking of nano-VCR will minimize the premature drug release during circulation but allow instant drug release at tumor sites or in tumor cells, therefore will greatly improve the efficacy and toxicity profile; and (iii) N-acetyl cysteine, when administered to the animal 24 hrs after the initial administration of nano-VCR, will further improve its therapeutic index. Nano-VCR will be further decorated with a highly potent ligand to enhance their targeting capability to av3 integrin overexpressed in neovasculatures of neuroblastoma. In this proposal, these hypotheses will be tested in murine neuroblastoma tumor model. The project addresses a critical issue in neuroblastoma therapy to reduce drug toxicity and increase drug efficacy. State of the art design of the nanocarriers via engineering telodendrimers with well-defined structures represents the frontier development of the nanomedicine, in terms of multiple functions, fine-tunable and highly reproducible structure and properties. The use of reversibly crosslinked micelles with fine-tuned stability and on-demand drug releasing property to delivery VCR against neuroblastoma is highly innovative. It's an excellent approach to prevent pre-mature drug release during circulation and deliver high concentrations of drug to tumor site. It is expected that this research will lead to new approach for neuroblastoma therapy.
The proposed research will lead to the development of highly efficacious and less toxic nanoformulations of VCR (nano-VCR) for neuroblastoma therapy. Unique features of nano-VCR are: (i) the size of the micelle formulation of VCR is under 30 nm, which is more suitable for penetrating poorly permeable tumors including metastatic neuroblastoma; (ii) there is minimal premature drug release from the cross-linked nanoparticles in blood circulation; (iii) a highly potent av3 integrin targeting ligand will be used to facilitte in vivo delivery of nano-VCR to high-risk neuroblastoma; (iv) VCR resistance may be overcome by using these nanoparticles that are not recognized by P-glycoprotein, one of the main mediators of multidrug resistance, thereby resulting in an increased intracellular concentration of drugs; (v the stability and drug release of nano- VCR can be fine-tuned via different level of disulfide crosslinking, which will greatly improve the pharmacokinetics, efficacy and toxicity profile; and (vi) NAC will be used as an on-demand drug-release triggering agent to enhance the therapeutic efficacy of the nanoparticle drugs. We expect these smart nanoparticle drugs to be much more efficacious and less toxic than the conventional and liposomal VCR formulations. This project will have a tremendous impact on the improvement of survival rate and quality of life of pediatric patients with neuroblastoma.
| Xiao, Kai; Lin, Tzu-Yin; Lam, Kit S et al. (2017) A facile strategy for fine-tuning the stability and drug release of stimuli-responsive cross-linked micellar nanoparticles towards precision drug delivery. Nanoscale 9:7765-7770 |
