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Synergistic Combination Chemotherapy of Lung Cancer: Cisplatin and Doxorubicin Conjugated Prodrug Loaded, Glutathione and Ph Sensitive Nanocarriers

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Synergistic Combination Chemotherapy of Lung Cancer: Cisplatin and Doxorubicin Conjugated Prodrug Loaded, Glutathione and Ph Sensitive Nanocarriers Drug Design, Development and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Synergistic Combination Chemotherapy of Lung Cancer: Cisplatin and Doxorubicin Conjugated Prodrug Loaded, Glutathione and pH Sensitive Nanocarriers This article was published in the following Dove Press journal: Drug Design, Development and Therapy Yonglong Jin1,* Purpose: Prodrug technology-based combination drug therapy has been exploited as Yi Wang2,* a promising treatment strategy to achieve synergistic lung cancer therapy, reduce drug Xiguang Liu1 dose, and decrease side effects. In the present study, we synthesized a pH and glutathione Jing Zhou1 (GSH) sensitive prodrug, cisplatin (CIS) and doxorubicin (DOX) conjugates (CIS-DOXp). Xintong Wang1 CIS-DOXp was loaded by nanocarriers and delivered into the tumor site. Methods: pH and GSH sensitive CIS-DOX prodrug (CIS-DOXp) was synthesized by con­ Hui Feng1 jugating GSH responsive CIS prodrug with pH sensitive DOX prodrug. CIS-DOXp-loaded Hong Liu2 nanocarriers (CIS-DOXp NC) were prepared using emulsification and solvent evaporation 1Department of Radiotherapy, Affiliated method. The morphology, particle size, polydispersity index (PDI) and zeta potential of nano­ Hospital of Qingdao University, Qingdao carriers were measured. In vitro cytotoxicity of nanocarriers and the corresponding free drugs 266000, People’s Republic of China; 2Department of Radiation Oncology, Qilu was examined using the MTT assay. In vivo anti-tumor efficiency and biodistribution behaviors Hospital of Shandong University, Jinan were evaluated on lung cancer mice models. 250012, People’s Republic of China Results: The size, PDI, zeta potential, CIS loading efficiency, and DOX loading efficiency *These authors contributed equally to of CIS-DOXp NC were 128.6 ± 3.2 nm, 0.196 ± 0.021, 15.7 ± 1.7 mV, 92.1 ± 2.1%, and 90.4 this work ± 1.8%, respectively. The best cell killing ability (the lowest combination index of 0.57) was found at the combination ratio of 1:3 (CIS:DOX, w/w) in the drugs co-loaded formulations, indicating the strongest synergism effect. CIS-DOXp NC showed the best tumor inhibition efficiency (79.9%) in mice with negligible body weight lost. Conclusion: CIS-DOXp NC could be applied as a promising system for the synergistic chemotherapy of lung cancer. Keywords: lung cancer, combination therapy, prodrug, pH responsive, GSH responsive Introduction Lung cancer is the leading cause of cancer-related death in the United States and worldwide, and this accounts for about 24% of all cancer deaths in USA.1,2 Poor diagnosis and limited therapeutic therapies have led to mostly evolved advanced- stage lung cancer patients and lower five-year survival rates (only 19%).3 It is generally known that systemic therapy is the most commonly applied therapeutic Correspondence: Hong Liu regimen for advanced or metastatic lung cancer patients. Whereas, chemotherapy Department of Radiation Oncology, Qilu Hospital of Shandong University, No. 107 regimens have faced various challenges hindering efficacy, including lack of tumor- West Wenhua Road, Jinan, Shandong, targeting, serious toxic effects on healthy tissues, and multidrug resistance.4,5 People’s Republic of China Email [email protected] Recently, researchers have devoted into new strategies to solve the aforementioned submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2020:14 5205–5215 5205 DovePress © 2020 Jin et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php http://doi.org/10.2147/DDDT.S260253 and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Jin et al Dovepress issues containing prodrug technology-based combination cancer and drug-resistance lung cancer cells. Tumor- therapy, and novel nanoscale targeting approaches (target­ bearing mice were utilized to determine the in vivo anti- ing the tumor microenvironment, such as the acidic pH, cancer efficiency and systemic toxicity drug forms. high concentration of glutathione, etc).6–9 Prodrug technology-based combination drug therapy Materials and Methods has been exploited as a promising treatment strategy to Materials achieve synergistic cancer therapy, minimal drug dose, and CIS, DOX, 1-(3-Dimethylaminopropyl)-3-ethylcarbodii­ 10,11 decreased side effects. Prodrug technology-based mide hydrochloride (EDC), glyceryl monostearate (GMS), combination drug therapy consists of at least three types and soya lecithin (SL) were obtained from Sigma-Aldrich of systems: two independent anticancer prodrugs; one free China (Shanghai, China). Compound 1 (Figure 1) was anticancer drug and another prodrug; and conjugates com­ purchased from TCI China. RPMI Medium 1640, fetal 11 posed of two different anticancer drugs. In the present bovine serum (FBS) and 3-(4,5-dimethyl-2-thiazolyl)- study, we synthesized a pH sensitive and glutathione 2,5-diphenyl-2-H-tetrazolium bromide (MTT) were pur­ (GSH) sensitive prodrug, cisplatin (CIS) and doxorubicin chased from Invitrogen Corporation (Carlsbad, CA). (DOX) conjugates. CIS is recommended as the first-line therapy for lung cancer by the NCCN guidelines. CIS is Synthesis of pH and GSH Sensitive a DNA alkylating agent, can bind with genomic DNA and interfere with normal transcription and/or DNA replica­ CIS-DOX Prodrug tion, thus triggering toxicity.12 DOX, a broad-spectrum GSH and pH sensitive CIS-DOX prodrug (CIS-DOXp) antitumor chemotherapeutic drug, has been applied in the was synthesized by conjugating GSH sensitive CIS pro­ treatment of a variety of cancers.13 CIS has been combined drug with pH sensitive DOX prodrug (Figure 1). 23,24 with DOX for lung cancer therapy, showing a significant Firstly, GSH sensitive CIS prodrug was synthesized. therapeutic effect.14–16 As is well known that both CIS and CIS was treated with hydrogen peroxide to obtain Pt(NH3)2 DOX are hydrophobic agents, pH and GSH sensitive CIS- Cl2(OH)2. Pt(NH3)2Cl2(OH)2 (1 equivalent) was reacted DOX prodrug has the similar properties and could be with Compound 1 (2.2 equivalents) overnight to form loaded by nanocarriers and delivered into the tumor site. Pt(NH3)2Cl2(OCOC6H12COOH)2. For stimuli-responsive nanocarriers, anti-cancer agents Secondly, pH sensitive DOX prodrug was 20,25 can be delivered and release at targeting locations to reach synthesized. Adipohydrazide (1 equivalent) and EDC ideal therapeutic anticipation. Among the common stimuli- (2 equivalents) were reacted in water solution at room tem­ triggered strategies, pH sensitive is the most frequently perature for 6 h. DOX (1.2 equivalents) was then added and researched and used in recent cancer therapy fields.17 reacted under acid conditions overnight to form DOX Prodrug-based pH sensitive nanoparticles can be achieved prodrug. by sensitive chemical linkers such as hydrazone bonds, Finally, DOX prodrug (2 equivalents) was activated by acetal linkage, etc.18–20 In our study, DOX and CIS were EDC (3 equivalents) and Pt(NH3)2Cl2(OCOC6H12COOH)2 conjugated by the hydrazone bond and GSH sensitive linker. (1 equivalent) was added and reacted overnight to get CIS- It is known that the GSH concentration in tumor cells is at DOXp. The structure of CIS-DOXp was determined by 1 least two-folds that for normal cells and intracellular GSH in LC-MS and H NMR. cisplatin-resistant cells is two-folds as high as that in cispla­ tin-sensitive cells.21,22 Therefore, nanocarriers that loaded Construction of CIS-DOXp-Loaded CIS-DOX pH sensitive and GSH sensitive prodrug (CIS- Nanocarriers DOXp) were exploited to realize double efficiencies. CIS-DOXp NC was prepared using emulsification and the Lipid nanocarriers were designed to encapsulate the solvent evaporation method.26,27 CIS-DOXp (20 mg), previously prepared CIS-DOXp. The drug ratios of CIS GMS (50 mg) and soya lecithin (100 mg) were dissolved to DOX were evaluated by combination index and the in chloroform (10 mL) to produce an oil phase. The oil physicochemical propriety of CIS-DOXp loaded nanocar­ phase was added to an aqueous phase containing Tween 80 riers (CIS-DOXp NC). Release studies were applied in (1.5%) and homogenized (10,000 rpm for 3 min) to get an GSH contained medium at different pH values. In vitro emulsion. The emulsion was sonicated for 5 min to obtain cytotoxicity of CIS-DOXp NC was evaluated for lung CIS-DOXp NC. 5206 submit your manuscript | www.dovepress.com Drug Design, Dev elopment and Therapy 2020:14 DovePress Dovepress Jin et al Figure 1 Synthesis of pH and GSH sensitive CIS-DOX prodrug (CIS-DOXp): CIS-DOXp was synthesized by conjugating GSH sensitive CIS prodrug with pH sensitive DOX prodrug. Non-prodrug contained nanocarriers were prepared 37°C for various time periods, monitoring the particle size using the same method using CIS (5 mg) and DOX changes. (15 mg) instead of CIS-DOXp (20 mg), namely CIS/ DOX NC; using CIS (10 mg) instead of CIS-DOXp Drug Loading and Drug Release in vitro (20 mg), namely CIS NC; using DOX (30 mg) instead of To determine the drug loading, nanocarriers ethanol solu­ CIS-DOXp (20 mg), namely DOX NC. Blank nanocarriers tion (1 mL) was centrifuged at 15, 000 rpm for 10 min and (NC) were prepared using the same method without the dissolved in 10 mL KOH (1 M) for 2 h. Then, HCl presence of any drug. (10 mL, 1.0 M) was added for neutralizing.30 The suspen­ Morphology, Particle Size, and Zeta sion was centrifuged at 15, 000 rpm for 10 min, followed by collecting and the upper clear solutions.
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