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In Vitro and in Vivo Assessments International Journal of Nanomedicine Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Lipoparticles for Synergistic Chemo-Photodynamic Therapy to Ovarian Carcinoma Cells: In vitro and in vivo Assessments This article was published in the following Dove Press journal: International Journal of Nanomedicine Sajid Ali1 Purpose: Lipoparticles are the core-shell type lipid-polymer hybrid systems comprising Muhammad Umair Amin1,2 polymeric nanoparticle core enveloped by single or multiple pegylated lipid layers (shell), Imran Tariq1,3 thereby melding the biomimetic properties of long-circulating vesicles as well as the Muhammad Farhan Sohail4,5 mechanical advantages of the nanoparticles. The present study was aimed at the development Muhammad Yasir Ali1,6 of such an integrated system, combining the photodynamic and chemotherapeutic approaches for the treatment of multidrug-resistant cancers. Eduard Preis1 Methods: For this rationale, two different sized Pirarubicin (THP) loaded poly lactic-co-glycolic Ghazala Ambreen1 1 acid (PLGA) nanoparticles were prepared by emulsion solvent evaporation technique, whereas Shashank Reddy Pinnapireddy liposomes containing Temoporfin (mTHPC) were prepared by lipid film hydration method. 1 Jarmila Jedelská Physicochemical and morphological characterizations were done using dynamic light scattering, 1 Jens Schäfer laser doppler anemometry, atomic force microscopy, and transmission electron microscopy. The 1 Udo Bakowsky quantitative assessment of cell damage was determined using MTT and reactive oxygen species 1Department of Pharmaceutics and (ROS) assay. The biocompatibility of the nanoformulations was evaluated with serum stability Biopharmaceutics, University of Marburg, testing, haemocompatibility as well as acute in vivo toxicity using female albino (BALB/c) mice. 2 Marburg, Germany; Faculty of Pharmacy, Results and Conclusion: The mean hydrodynamic diameter of the formulations was The University of Lahore, Lahore, Pakistan; 3Punjab University College of Pharmacy, found between 108.80 ± 2.10 to 405.70 ± 10.00 nm with the zeta (ζ) potential ranging University of the Punjab, Allama Iqbal from −12.70 ± 1.20 to 5.90 ± 1.10 mV. Based on the physicochemical evaluations, the Campus, Lahore, Pakistan; 4Riphah Institute of Pharmaceutical Sciences (RIPS), Riphah selected THP nanoparticles were coated with mTHPC liposomes to produce lipid-coated International University, Lahore, Pakistan; nanoparticles (LCNPs). A significant (p< 0.001) cytotoxicity synergism was evident in 5 Department of Pharmacy, Faculty of Health LCNPs when irradiated at 652 nm, using an LED device. No incidence of genotoxicity and Medical Science, University of Copenhagen, Copenhagen, Denmark; was observed as seen with the comet assay. The LCNPs decreased the generalized in vivo 6Faculty of Pharmaceutical Sciences, GC toxicity as compared to the free drugs and was evident from the serum biochemical University Faisalabad, Faisalabad, Pakistan profile, visceral body index, liver function tests as well as renal function tests. The histopathological examinations of the vital organs revealed no significant evidence of toxicity suggesting the safety and efficacy of our lipid-polymer hybrid system. Keywords: atomic force microscopy, FACS, in vivo, in vitro cytotoxicity, lipid-polymer hybrid nanoparticles, photodynamic therapy, PLGA nanoparticles, TEM Introduction The combination therapy is referred to as the simultaneous administration of two or Correspondence: Udo Bakowsky Department of Pharmaceutics and more pharmacologically active moieties which can alter the different signaling Biopharmaceutics, University of Marburg, pathways in the infectious sites.1 The anticancer combination therapy has been Robert Koch Str. 4, Marburg, 35037, Germany proved to be an effective treatment strategy than the delivery of the single drug Tel + 49 6421 28 25884 modality. This therapy can significantly reduce the side effects, increase the treat­ Fax + 49 6421 28 27016 Email [email protected] ment efficacy, and potentially overcome the multidrug resistance, which could be submit your manuscript | www.dovepress.com International Journal of Nanomedicine 2021:16 951–976 951 DovePress © 2021 Ali 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/IJN.S285950 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). Ali et al Dovepress a major limiting factor to the success of anticancer The present study was focused on the development of chemotherapy.2,3 To accomplish an effective enhancement, novel lipid-coated biodegradable nanoparticles (LCNP) con­ both the therapeutic moieties (with the different mechan­ sisting of a nanoparticle core surrounded by a liposomal isms of actions) shall be co-localized in the cancer cells. In membrane (Figure 1). This nanocarrier system was devel­ such therapeutic systems, the increased potency of the oped to provide a synergistic therapy to the cancer cells by anticancer drugs can be observed at the lower effective concurrently delivering two different drugs. THP and dose that corresponds to the reduction in the cancer cell mTHPC loaded formulations were evaluated using dynamic viability or tumor volume as compared to two separate light scattering (DLS) and laser doppler anemometry (LDA) administered treatments.2 The combination of chemother­ for size distribution and surface charge, respectively. apy and photodynamic therapy has emerged as Morphological characterizations were carried out using a promising strategy for the treatment of the cancer. atomic force microscopy (AFM) and transmission electron Pirarubicin ([2″R]-4′-O-tetrahydropyranyl-doxorubicin; microscopy (TEM). Besides, the in vitro cell viability assay THP) is an anthracycline derivative that inhibits type II was conducted using ovarian carcinoma (SK-OV-3) cells topoisomerase and DNA polymerase. It is used for the and IC50 values for the THP loaded PLGA nanoparticles, treatment of a variety of cancers such as head, neck, breast, mTHPC loaded liposomes, as well as lipid-coated nanopar­ and lymphomas. THP is a pyranyl derivative of doxorubicin ticles (LCNPs), were calculated. In vitro hemocompatibility involving the generation of reactive oxygen species (ROS). using activated partial thromboplastin time (aPTT) and ex- Due to the presence of the pyranyl group and its lipophilic vivo hemolysis assay was determined. Stability studies in properties, it exhibits a more potent anticancer activity and simulated physiological conditions were also performed. faster cellular uptake than doxorubicin.4 The limitation of Acute in vivo toxicity assessment including blood biochem­ the THP mediated chemotherapy is the indiscriminate dis­ istry and histopathological examinations were conducted tribution into normal body tissues and organs before its using albino female albino (BALB/c) mice. delivery to the tumor thus causing adverse effects such as bone marrow suppression and cardiac and renal toxicity. All Materials and Methods these adverse effects limit the use of THP in clinical Materials 5 settings. The pharmacokinetic parameters of THP can be Pirarubicin ([2″R]-4′-O-tetrahydropyranyl-doxorubicin; modified by encapsulating it into a nanoparticulate system THP) (98% pure) was purchased from Selleckchem thus reducing the side effects and increasing the efficacy of (Absource diagnostics, München, Deutschland). the system. Nanocarriers composed of PLGA (Poly-D, Temoporfin (5, 10, 15, 20-tetrakis (3-hydroxyphenyl) L-lactide-co-glycolide) have been investigated to carry the chlorin; mTHPC) was procured from Cayman chemicals drugs to their designated site of action. Being biocompatible (Hamburg, Germany). 1,2-dipalmitoyl-sn-glycero-3-phos­ and biodegradable, PLGA nanoparticles are interesting vehi­ phatidylcholine (DPPC); 1,2-dipalmitoyl-sn-glycero-3-phos­ 6 cles for the systemic delivery of THP. phoethanolamine-N-[methoxy(polyethylene glycol)-5000] Temoporfin (Meso-tetrahyroxyphenyl chlorine; mTHPC) (DPPE-mPEG5000) and 2-dipalmitoyl-sn-glycero-3-phos­ is one of the most potent second-generation photosensitizers pho-(1′-rac-glycerol) (sodium salt) (DPPG) were obtained used for the treatment of a variety of clinical disorders. After as gift sample from Lipoid GmbH (Ludwigshafen, being administered, the mTHPC can be preferentially loca­ Germany). PLGA (Resomer® RG 503 H, Poly (D, L-lactide- lized into the tumor tissue by exploiting the tumor′s EPR co-glycolide)) was supplied by Evonik (Essen, Germany). (enhanced permeability and retention) effect. After being Poly (vinyl alcohol) (PVA, Mowiol 4–88) was purchased activated by a specific wavelength (652 nm), it produces from Kuraray (Hattersheim, Germany). Polysorbate 80 free radicals and singlet oxygen species that caused the (Tween 80); 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetra­ destruction of cancer cells.7 However, its hydrophobic nat­ zolium bromide (MTT) and 2′,7′-dichlorodihydrofluorescein ure, poor aqueous solubility, and low
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