Copper−Doxorubicin as a Nanoparticle Cargo Retains Efficacy with Minimal Toxicity

Abstract

Repeated administration of chemotherapeutics is typically required for the effective treatment of highly aggressive tumors and often results in systemic toxicity. We have created a copper-doxorubicin complex within the core of liposomes and applied the resulting particle in multi-dose therapy. Copper and doxorubicin concentrations in the blood pool were similar at 24 hours (~40% of the injected dose) indicating stable circulation of the complex. Highly-quenched doxorubicin fluorescence remained in the blood pool over tens of hours, with fluorescence increasing only with the combination of liposome disruption and copper trans-chelation. At 48 hours after injection, doxorubicin fluorescence within the heart and skin was one-fifth and one-half, respectively, of fluorescence observed with ammonium sulfate-loaded doxorubicin liposomes. After 28 days of twice per week doxorubicin administration of 6 mg/kg, systemic toxicity (cardiac hypertrophy and weight and hair loss) was not detected with the copper-doxorubicin liposomes but was substantial with ammonium sulfate-loaded doxorubicin liposomes. We then incorporated two strategies designed to enhance efficacy, mTOR inhibition (rapamycin) to slow proliferation and therapeutic ultrasound to enhance accumulation and local diffusion. Tumor accumulation was ~10% ID/g and was enhanced approximately two-fold with the addition of therapeutic ultrasound. After the 28-day course of therapy, syngeneic tumors regressed to a pre-malignant phenotype of ~ (1 mm)3 or could not be detected.

Ultrasound ablation enhances drug accumulation and survival in mammary carcinoma models

“…The disadvantage of this approach is that the particles typically have a shorter circulation half-life as compared with other nanoformulations. We have previously shown that a highly effective formulation of temperature-sensitive doxorubicin particles could be synthesized with a 1.5-hour circulation half-life (as compared with an ~20 hour circulation half-life for long-circulating particles) (12,40). We showed that the free drug was released only in the presence of heat and reduced pH and therefore systemic toxicity was reduced.…”

“…Liposomes used here included 64 Cu-labeled empty LCL, doxorubicin-loaded LCL and TSL, and Alexa Fluor 555-loaded (A555-loaded) LCL. Dox-LCL was prepared using copper for stabilization, a formulation that reduces systemic toxicity by encapsulating nonbioactive copper-doxorubicin crystals (40) that dissociate in the low pH of the tumor microenvironment (40,51). Copper-doxorubicin TSLs (Dox-TSL) demonstrate increased circulating stability and similarly reduced systemic toxicity (12).…”

Classification of stimuli–responsive polymers as anticancer drug delivery systems

“…Ultrasound-dependent drug release can be achieved through the thermal and/or mechanical effects generated by cavitation phenomena or radiation forces. It has been shown that physical forces associated with cavitation can cause nanocarrier destabilization and subsequent drug release (Schroeder et al, 2009) and also that a transient increase in vessels permeability by the application of therapeutic ultrasound lead to twofold increase in tumor accumulation of anticancer drug molecules (Kheirolomoom et al, 2010).…”

Phase-transition Perfluorocarbon Nanoparticles for Ultrasound Molecular Imaging and Therapy

“…Kheirolomoom et al have reported that the development of ultrasound-reduced stable liposomes could prolong circulation time and accelerate tumor targeting [20,86,87]. Ultrasound-responsive cavitation has also been used to enhance permeabilization of cell membranes [88,89].…”

“…During the last decade, advances in nanomedicine have permitted nanoparticles encapsulated various imaging agents, targeting moieties and therapeutic drugs to be a container of various functionalities [5,[16][17][18][19][20][21][22][23]. One of the most promising examples is the perfluorocarbon (PFC) nanoparticles, because its characters of nontoxic biocompatibility and low solubility in aqueous liquids are extremely essential for medical application [24][25][26][27].…”