Enhanced solubility and functionality of valrubicin (AD-32) against cancer cells upon encapsulation into biocompatible nanoparticles

Abstract

Among numerous drug-delivery approaches, reconstituted high-density lipoprotein (rHDL) nanocarriers have proven particularly applicable for delivering highly hydrophobic drugs. In this study, we have investigated the enhancement of the therapeutic impact of valrubicin (AD-32), an antineoplastic agent that has been limited to intravesicular application against bladder cancer, despite the encouraging original preclinical data. Earlier studies validated the superior therapeutic efficacy of AD-32 over doxorubicin. In the present study, rHDL/AD-32 nanoparticles were formulated and characterized with regard to encapsulation efficiency, physicochemical properties, selective toxicity, and receptor-mediated uptake. The half maximal inhibitory concentration values (IC 50 ) for rHDL/AD-32 nanoparticles were 1.8 and 2.6 times lower than the free AD-32 for prostate (PC-3) and ovarian (SKOV-3) cancer cell lines, respectively, whereas nonmalignant cell lines demonstrated 5 and 1.48 times higher IC 50 doses with rHDL/AD-32 formulations. The data obtained demonstrated effective receptor-mediated uptake of AD-32 from the rHDL nanocarriers by PC-3 and SKOV-3 cancer cells via a targeted drug-delivery process. The rHDL/AD-32 formulation was stable for 6 months when stored at 4°C or at -20°C, as 92% of the AD-32 was retained in the nanoparticles. The findings from this study show that the rHDL/AD-32 formulation can overcome the solubility barriers of AD-32 and thus serve as an effective systemically administered chemotherapeutic agent.

Targeting the SR-B1 Receptor as a Gateway for Cancer Therapy and Imaging

“…Using a quantitative real-time PCR technique, Shahzad et al (2011) have demonstrated considerable increase in the expression of SR-B1 receptors in most tumor samples of breast, ovarian, colorectal and pancreatic cancer compared with those of normal tissues (Shahzad et al, 2011). The SR-B1 mediated process has also been shown to function in the uptake of anticancer agents from reconstituted high density lipoprotein (rHDL) by cancer cells (McConathy et al, 2008; Mooberry et al, 2010; Sabnis et al, 2012; Shen et al, 2014; Song et al, 2015). An enhanced uptake of paclitaxel from rHDL nanoparticles was demonstrated in SR-B1 overexpressing prostate cancer cells by Mooberry et al (2010) where the SR-B1 mediated entry of the drug represented 82% of the total paclitaxel incorporation by these cells.…”

Lipoproteins and lipoprotein mimetics for imaging and drug delivery

“…[73] SR-B1 has been implicated in cancer and serves as a mechanism for HDL-based agents to target tumors. [74]…”

“…[159] Uptake of HDL cargo, including anticancer drugs, occurs through a non-endocytic pathway. [74, 160] This is highly desirable for drug delivery, as endosomal uptake of drug-loaded nanoparticles typically leads to lysosomal degradation of both the drug and the delivery vehicle.…”

“…In a recent report, Lacko et al sequestered the poorly water soluble drug valrubicin into spherical HDL. [74, 165] This drug loaded HDL had significantly increased toxicity against SR-B1 expressing ovarian and prostate cancer cell lines, compared to valrubicin alone. Drug toxicity in normal prostate and ovarian epithelial cell lines was reduced in the HDL-drug formulation compared to drug alone.…”

High-density lipoproteins for therapeutic delivery systems

“…As a marker of tolerability, the rHDL-formulated PTX induced less weight loss in treated mice as compared to unformulated drug. Using similar approaches, Sabnis, et al have formulated the chemotherapeutic valrubicin into spherical rHDLs 73 , as well as fenretinide, a retinoid, potentially useful in neuroblastoma. 74 …”