Engineered Polymeric Micelles for Combinational Oxidation

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Engineered polymeric micelles for combinational oxidation anticancer therapy through concurrent HO-1 inhibition and ROS generation Joungyoun Noh, Eunkyeong Jung, Jeonghun Lee, Hyejin Hyun, Seri Hong, and Dongwon Lee Biomacromolecules, Just Accepted Manuscript • Publication Date (Web): 03 Jan 2019 Downloaded from http://pubs.acs.org on January 3, 2019

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Biomacromolecules

Engineered polymeric micelles for combinational oxidation anticancer therapy through concurrent HO-1 inhibition and ROS generation Joungyoun Noh a, Eunkyeong Jung b, Jeonghun Lee b, Hyejin Hyun b, Seri Hong b, Dongwon Lee a,b,*

a Department

of PolymerNano Science and Technology, Chonbuk National University,

Baekjedaero 567, Jeonju, Chonbuk, 54896, Republic of Korea

b Department

of BIN Convergence Technology, Chonbuk National University, Baekjedaero

567, Jeonju, Chonbuk, 54896, Republic of Korea

Corresponding Author

ACS Paragon Plus Environment

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*E-mail: [email protected],

ABSTRACT

Cancer cells have a large amount of ROS (reactive oxygen species) because of disturbed ROS homeostasis. Cancer cells therefore undertake redox adaptation to drive proliferation in tumor environments and even survive during anticancer treatment by upregulating endogenous antioxidants. As one of antioxidant defense systems, heme oxygenase-1 (HO-1) acts as essential roles in tumor development by offering antioxidant bilirubin to protect cancer cells under stress conditions. It can be therefore reasoned that the combination of ROS generation and HO-1 inhibition would exert synergistic anticancer effects through the amplification of oxidative stress and provide a new opportunity for targeted anticancer therapy. To establish targeted anticancer therapy based on amplified oxidative stress, we developed molecularly engineered polymer, termed CZP, which incorporates ROS generating CA (cinnamaldehyde) and HO-1 inhibiting ZnPP (zinc protoporphyrin) in


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its backbone and could form stable micelles in aqueous solutions. CZP micelles not only elevated oxidative stress but also suppressed the expression of antioxidant HO-1, leading to apoptotic cell death. CZP micelles could also significantly suppress the tumor growth without body weight loss, tumor recurrence and noticeable toxicity in organs. This study demonstrates that combination of ROS generation and HO-1inhibition synergistically magnifies oxidative stress to kill cancer cells and oxidative stress amplifying CZP micelles may provide a promising strategy in anticancer treatment.

Keywords: oxidative stress; oxidation anticancer therapy; cancer; micelles; heme oxygenase-1 1. Introduction In spite of substantial improvement in the drug discovery, molecular biology and oncology over the past decade, cancer is as one of the major causes of death worldwide as ever.1-3 One of the straightforward and powerful approaches for cancer treatment is chemotherapy using various



anticancer drugs, but most anticancer drugs have some limitations for instance, deficient bioavailability, lack of target specificity, the possibility to induce multidrug resistance and adverse side effects.2,4 To get over these shortcomings, extensive efforts have been dedicated to developing effective anticancer therapeutic strategy. “Oxidation therapy” is one of the recently developed anticancer therapies and has gained increasing attractions.5-7 Oxidation therapy exploits the redox imbalance in cancer cells. In comparison with normal cells, cancer cells have an elevated level of ROS such as singlet oxygen, hydrogen peroxide and hydroxyl radicals and therefore are under oxidative stress.7-8 Although the intracellular level of ROS in cancer cells are not exactly determined, almost all cancer cells are known to have excessive ROS such as prostate cancer cells and colorectal cancer cells.9-11 Cancer cells are hence more easily affected by therapeutic agents including arsenic trioxide (As2O3), cisplatin, glucose oxidase and cinnamaldehyde that stimulate ROS generation to kill cancer cells preferentially.5,12-13 On the other hand, quinone methide (QM), -phenylethyl isocyanate and buthionone sulfoximine were reported to deplete antioxidant defense systems and exacerbate the redox imbalance in cancer cells, giving rise to cell death.14-18 One of promising and powerful approaches to maximize oxidative stress in anticancer treatment would be the combination of ROS generation and antioxidant depletion.6,12,15,19 Concurrent delivery of ROS generators and antioxidant inhibitors to cancer cells could drastically amplify the oxidative stress to kill cancer cells and could be referred to as “combinational oxidation anticancer therapy”. Various combinations of ROS-generating compounds and antioxidant-inhibiting compounds could be made to achieve synergistic effects in the amplification of oxidative stress, targeting selective destruction of cancer cells.4,15 In this work, cinnamaldehyde (CA) and zinc


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protoporphyrin (ZnPP) were selected as a ROS-generating compound and antioxidant-inhibiting agent, respectively. CA is a major ingredient in cinnamon which has been extensively used in foods including beverage, ice cream and candies and herbal medicine.20-21 Accumulative evidence has demonstrated that CA and its derivatives trigger apoptosis of cancer cells through mitochondrial membrane disruption and caspase activation.22-24 On the other hand, ZnPP is known to elevate oxidative stress by depleting antioxidant heme oxygenase-1 (HO-1), which is a heme degrading enzyme. HO-1 is present at low concentration under normal conditions, but plays a vital role in tumor development by protecting cancer cells under stress conditions such as heat shock, hypoxia, high-energy radiation, ROS and heavy metals.15,25-26 It has been reported that cancer cells exploit the cytoprotective functions of HO-1 as a shield from chemo- and radiotherapy. Moreover, Maeda et al. have recently reported that ZnPP exerts potent anticancer activity by inhibiting HO-1 and also moderates the therapeutic responses of cancer cells to ROS generating anticancer drugs.27-28 Although a number of researchers have documented the therapeutic potential of CA and ZnPP in cancer treatment, it is necessary to develop methodologies to deliver CA and ZnPP concurrently to targeted cancer cells to maximize synergistic therapeutic effects and overcome their intrinsic limitations such as poor solubility, low bioavailability and lack of targetability.15,29-33 One of the promising strategies to address these challenges encountered in combinational oxidation anticancer therapy would be the covalent incorporation of both ROS generators and antioxidant inhibitors in the chain of stimulus-responsive biodegradable polymer.30,34 This strategy could realize the concurrent delivery of both therapeutic agents and high drug loading capacity and also enhance their bioavailability. On the basis of great therapeutic potential of CA and ZnPP and



the advantages of polymeric prodrugs, we developed CZP (CA and ZnPP-incorporated polymer) as a combinational oxidation anticancer therapeutic agent.

Scheme 1. A schematic diagram showing the construction of CZP micelles with their working mechanism of combinational oxidation anticancer therapy.

As illustrated in Scheme 1, CA is incorporated covalently in the poly(-amino ester) through the formation of acid-sensitive acetal linkages. ZnPP is also grafted to side chains of the polymer. CZP could form thermodynamically stable micelles through self-assembly in aqueous environments and be activated by acidic pH in cancer microenvironments to


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liberate CA and ZnPP. Therefore, the hypothesis behind the therapeutic actions of CZP micelles is that ZnPP-mediated inhibition of antioxidant HO-1 renders cancer cells highly vulnerable to CA-mediated ROS insults and therefore the elevated oxidative stress could induce preferential cancer cell death. In addition, CZP micelles with a mean diameter of

Engineered Polymeric Micelles for Combinational Oxidation

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