Development of medical-grade, discrete, multi-walled carbon nanotubes as drug delivery molecules to enhance the treatment of hematological malignancies
Carolyne R. Falank1,2,3, Aaron W. Tasset4, Sophie Harris1,2,3, Mariah Farrell1,2,3, Milos Marinkovic4, Michaela R. Reagan1,2,3
1Maine Medical Center Research Institute, Scarborough, ME 04074. 2University of Maine, Orono, Maine. 3Tufts University, Boston Massachusetts. 4BioPact Ventures, LLC, Austin, TX 78736.
Burkitt’s lymphoma is an aggressive B-cell derived non-Hodgkin lymphoma. Doxorubicin (Dox) constitutes a common therapy, but features numerous side effects, including significant weight and hair loss, myelotoxicity, cardiovascular damage and treatment-related leukemia. Tumor-specific delivery holds great promise for mitigating adverse side effects while maintaining therapeutic effectiveness of Dox. Carbon nanotubes (CNTs) are highly-prospective drug delivery vehicles due to their unique architecture, high drug-loading surface area and tunable chemistry. Unfortunately, in vivo toxicology, elicited by poor physiological solubility/clearance and high residual contaminants, has prohibited clinical translation of CNTs. XACT™ is a novel drug delivery technology which overcomes these obstacles by utilizing purified, discrete CNTs (dCNTs), bio-compatibilized and highly stable in vivo.
To evaluate long-term stability of dCNTs in physiological conditions, zeta potential (-40 to -50 mV) analysis were performed in ionic, high-serum solutions. No toxicity of dCNTs was observed across multiple cell types in vitro or in murine in vivo models, establishing a high MTD of 70 mg/kg for IV administration. Biodistribution studies (34 days) were conducted in female BALB/C mice using radioisotope-labeled dCNTs. Approximately 60% of injected dCNTs were retained in bone, while the remaining fraction demonstrated high-tolerability and clearance from various organs. Critically, in vitro drug delivery studies showed that dCNT endocytosis is non-cytotoxic and unloaded cargos retain functionality.
We evaluated the considerable potential of dCNTs for bone-specific drug delivery in a murine Raji-Burkitt’s lymphoma model. Whole body bioluminescence imaging revealed that, similarly to those treated with free Dox, groups receiving the Dox-loaded dCNTs showed greatly reduced tumor burden compared to untreated. However, the group receiving Dox-loaded dCNTs also demonstrated increased survival compared to free Dox. Furthermore, typical murine indications of Dox toxicity, characterized by rapid weight loss or drug-related mortality, were not observed in groups receiving Dox-loaded CNTs indicating dCNT’s ability to mitigate negative side effects while retaining efficacy.
In summary, XACT™ dCNTs are a highly-stable, nontoxic and versatile vehicle, featuring a promising capability for targeted delivery to bone tissue. This novel technology provides considerable clinical potential as a therapeutic delivery mechanism for diseases of bone and bone marrow, but also for osteoregenerative applications.