Abstract
Drug resistance always reduces the efficacy of chemotherapy, and the classical mechanisms of drug resistance include drug pump efflux and anti-apoptosis mediators-mediated non-pump resistance. In addition, the amphiphilic polymeric micelles with good biocompatibility and high stability have been proven to deliver the drug molecules inside the cavity into the cell membrane regardless of the efflux of the cell membrane pump. We designed a cyclodextrin (CD)-based polymeric complex to deliver chemotherapeutic doxorubicin (DOX) and Nur77ΔDBD gene for combating pumps and non-pump resistance simultaneously. The natural cavity structure of the polymeric complex, which was comprised with β-cyclodextrin-graft-(poly(ε-caprolactone)-adamantly (β-CD-PCL-AD) and β-cyclodextrin-graft-(poly(ε-caprolactone)-poly(2-(dimethylamino) ethyl methacrylate) (β-CD-PCL-PDMAEMA), can achieve the efficient drug loading and delivery to overcome pump drug resistance. The excellent Nur77ΔDBD gene delivery can reverse Bcl-2 from the tumor protector to killer for inhibiting non-pump resistance. The presence of terminal adamantyl (AD) could insert into the cavity of β-CD-PCL-PDMAEMA via host-guest interaction, and the releasing rate of polymeric inclusion complex was higher than that of the individual β-CD-PCL-PDMAEMA. The polymeric inclusion complex can efficiently deliver the Nur77ΔDBD gene than polyethylenimine (PEI-25k), which is a golden standard for nonviral vector gene delivery. The higher transfection efficacy, rapid DOX cellular uptake, and significant synergetic tumor cell viability inhibition were achieved in a pump and non-pump drug resistance cell model. The combined strategy with dual drug resistance mechanisms holds great potential to combat drug-resistant cancer.
Highlights
Despite the ongoing efforts to develop novel anticancer drugs to fight various types of cancers, drug resistance still leads to a high mortality rate of patients [1,2,3,4]
Multidrug resistance mediated by P-gp, known as multidrug-resistant protein 1 (MDR1) encoded by ATP-binding cassette (ABC) subfamily member 1 (ABCB1), is the most common in clinical therapy of liver, kidney, and colon cancer, which endows cancer cells an ability to excrete exogenous chemotherapeutic drugs [16]
The presence of AD helped the β-CD-PCL-AD polymer to insert into the cyclodextrin cavity of β-CD-PCL-PDMAEMA, greatly increasing the possibility of cross-linking and the space for drug loading
Summary
Despite the ongoing efforts to develop novel anticancer drugs to fight various types of cancers, drug resistance still leads to a high mortality rate of patients [1,2,3,4]. Drug efflux mediated by ATP-binding cassette (ABC) drug transporters is an essential reason of MDR in many chemotherapeutic drugs [12,13,14]. These drug transporters are generally overexpressed on the membrane surface of drug-resistant cancer cells. Multidrug resistance mediated by P-gp, known as multidrug-resistant protein 1 (MDR1) encoded by ABC subfamily member 1 (ABCB1), is the most common in clinical therapy of liver, kidney, and colon cancer, which endows cancer cells an ability to excrete exogenous chemotherapeutic drugs (i.e., doxorubicin) [16]. Orphan nuclear receptor Nur ( named as TR3/NGFI-B) has been proven to be located between the BH3 and BH4 domains of mitochondrial Bcl-2 protein to change the conformation of the Bcl-2 protein family, reversing the anti-apoptotic mechanism into a pro-apoptotic one, which might be a solution to overcome non-pump resistance [25,26]
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