Multidrug Delivery Systems Based on Human Serum Albumin for Combination Therapy with Three Anticancer Agents

Abstract

When administering several anticancer drugs within a single carrier, it is important to regulate their spatial distribution so as to avoid possible mutual interference and to thus enhance the drugs' selectivity and efficiency. To achieve this, we proposed to develop human serum albumin (HSA)-based multidrug delivery systems for combination anticancer therapy. We used three anticancer agents (an organic drug [5-fluorouracil, or 5FU], a metallic agent [2-benzoylpyridine thiosemicarbazide copper II, or BpT], and a gene agent [AS1411]) to treat liver cancer and confirm our hypothesis. The structure of the HSA-palmitic acid (PA)-5FU-BpT complex revealed that 5FU and BpT, respectively, bind to the IB and IIA subdomains of HSA. Our MALDI-TOF-MS spectral data show that one AS1411 molecule is conjugated to Cys-34 of the HSA-5FU-BpT complex via a linker. Compared with unregulated three-drug combination therapy, the HSA-5FU-BpT-AS1411 complex enhances cytotoxicity in Bel-7402 cells approximately 7-fold in vitro; however, in normal cells it does not raise cytotoxicity levels. Importantly, our in vivo results demonstrate that the HSA-5FU-BpT-AS1411 complex is superior to the unregulated three-drug combination in enhancing targeting ability, inhibiting liver tumor growth, and causing fewer side effects.

Strategies for Preparing Albumin-based Nanoparticles for Multifunctional Bioimaging and Drug Delivery

“…Ferric anticancer agents were also reported to bind to albumin and inhibit tumor growth in vivo 175 . Three anti-tumor drugs, namely, 5-fluorouracil, a copper (II)-based anti-tumor agent and a gene agent, were co-loaded in albumin by hydrophobic interaction or covalent conjugation 176 . The triple-drug combinatorial drug delivery system exhibited enhanced targeting ability and inhibition of liver tumor growth and showed few side effects.…”

HSA-based multi-target combination therapy: regulating drugs’ release from HSA and overcoming single drug resistance in a breast cancer model

“…Increasing evidences have revealed that a single anticancer drug that inhibits a pathway is not sufficient to achieve tumor recession due to several reasons: (1) cancers are complicated diseases that involve multiple pathways (Hanahan & Weinberg, 2011 ); and (2) cancer cells often have intrinsic and acquired resistance to chemotherapeutic agents (Baguley, 2010 ; Gandin et al., 2013 ; Santini et al., 2014 ). Currently, multi-drug combination therapy has been adopted to overcome the deficiency of a single anticancer drug since several agents can simultaneously modulate different signaling pathways in diseased cells (Aw et al., 2013 ; Ma et al., 2013 ; Qi et al., 2016b ; Huang et al., 2017 ).…”

l-Carnitine conjugated chitosan-stearic acid polymeric micelles for improving the oral bioavailability of paclitaxel

“…For the past few years, a large number of efforts have been paid to developing nanometer delivery system for improving the oral absorption of insoluble antitumor drugs, including micelles (Yao et al, 2017;Ma & Williams, 2018), liposomes (He et al, 2016;Hussain et al, 2016;Luo et al, 2016), nanogels (Voeikov et al, 2017), nanoparticles (Choi et al, 2014;Kang et al, 2015;Qi et al, 2016), and nanocrystals (Choi & Park, 2016. Polymeric micelle, as an ideal carrier of hydrophobic drugs, received increasing attentions due to their excellent properties, e.g.…”