Development of Lipid-based Nanocapsules of Novel Taxane Conjugates to Improve Treatment of Resistant and Metastatic Breast Cancer

S. Rahima Benhabbour
University of North Carolina at Chapel Hill, US

Keywords: cancer nanotechnology

Summary:

Breast cancer is the most diagnosed cancer in women and the second most common cause of female cancer-related deaths with over one million new cases reported per year worldwide. Despite advances in the early detection of breast cancer and the emergence of novel targeted therapies, progress in the medical treatment of metastatic breast cancer has shown very limited success due to the lack of agents which demonstrate effective targeting and a high therapeutic index. In addition, treatment of breast cancer is complicated by the fact that about half of all breast cancer patients will experience intrinsic or acquired multiple drug resistance (MDR) to the chemotherapeutic agent. The focus of the present work is to investigate lipid-based oil-filled nanocapsules containing a novel 2’-(2-halohexadecanoyl)-docetaxel conjugate (XHDX NPs; X = Br, Cl or F) to improve treatment of resistant and metastatic breast cancer. The lead nanosystem (BTM) was a lipid-based nanocapsule formulation comprised of a liquid Miglyol oil core and two surfactants (Brij 78 and vitamin E TPGS). Previous studies have demonstrated that ‘BTM’ nanocapsules can overcome at least two cancer-associated ABC-transport systems (MDR and MRP-associated) resulting in up to a 200-fold reduction in the IC50 values in in-vitro cytotoxicity studies using resistant human breast, lung, ovarian, leukemia, melanoma, and prostate cells. One limitation of the original ‘BTM’ formulation was the rapid drug release from the NPs, which reached >90% in plasma in less than 1-2 h. To improve in-vivo efficacy, we synthesized various lipid-ester prodrugs of PX and DX with enhanced affinity for the oil core of the BTM NPs. This work has led to the development of a modified and novel ‘BTM’ NP containing a novel 2’-Br-lipid ester of DX (2-Br-C16-DX, BHDX). In-vivo pharmacokinetic studies showed ~100-fold increase in the AUC0-∞ value of NP-formulated BHDX compared to DX in standard-of-care (SOC) treatment of Taxotere®, and tumor accumulation of BHDX was increased by >10-fold versus SOC treatment. However, the AUC0-96 of DX from BHDX NPs in the tumor was only 1.5-fold higher than that of Taxotere suggesting slow prodrug hydrolysis in-vivo. This limitation will be addressed by A) modifying the chemistry of the prodrug to further enhance hydrolysis, and B) increase uptake of NPs by tumor cells via specific targeting that can enhance prodrug hydrolysis under endosomal pH conditions. We will screen the selected XHDX-NPs in various sensitive and resistant breast cancer cell lines to determine their cytotoxicity and ability to overcome MDR both in-vitro and in-vivo. With the goal to enhance the therapeutic index of DX and other chemotherapeutics and advance the formulation to the clinic, we will also investigate enhanced uptake of the NPs in breast tumor cells via active targeting to specific receptors overexpressed in breast cancers with single modality or bispecific-like targeting strategies.