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Responsive Nanomicellar Theranostic Cages for Metastatic Breast Cancer Amrutha Manigandan, Vandhana Handi, Niranjana Sri Sundaramoorthy, Ramya Dhandapani, Janani Radhakrishnan, Swaminathan Sethuraman, and Anuradha Subramanian Bioconjugate Chem., Just Accepted Manuscript • DOI: 10.1021/acs.bioconjchem.7b00577 • Publication Date (Web): 27 Dec 2017 Downloaded from http://pubs.acs.org on December 28, 2017
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Bioconjugate Chemistry
Responsive Nanomicellar Theranostic Cages for Metastatic Breast Cancer †
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Amrutha Manigandan, Vandhana Handi, Niranjana Sri Sundaramoorthy, Ramya † † † † Dhandapani, Janani Radhakrishnan, Swaminathan Sethuraman, Anuradha Subramanian*,
Author affiliations: †
Centre for Nanotechnology & Advanced Biomaterials School of Chemical & Biotechnology, SASTRA Deemed University, Thanjavur 613 401, India.
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Corresponding Author:
Anuradha S. Ph. D. Assistant Professor (Research) Center for Nanotechnology & Advanced Biomaterials School of Chemical & Biotechnology SASTRA Deemed University Tamil Nadu, India Ph: +91 4362 – 264101 Extension 2348 Fax: +91 4362 264120 Email:
[email protected] 1 ACS Paragon Plus Environment
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Abstract Precluding the progression of metastasis with early-diagnosis of triple-negative breast cancer remains challenging due to lack of targeting specificity with poor diagnostic potential. Herein, an amphipathic chitosan-based targeted nanomicellar theranostics (30-45 nm) comprising doxorubicin–superparamagnetic iron oxide nanoparticles complexes (89.23%) with lower critical micelle concentration (0.1 µg/mL) were developed. Micelles exhibits concentrationbased contrast enhancement in MRI (r2 6.27mM-1s-1) and hyperthermia rather than thermalablation. This theranostics delivers Doxorubicin under alternating magnetic field (480 kHz) and at endosomal pH (pH 5.2) while showing stability at pH7.4. Anti-αvβ3 integrin antibody conjugation onto PEGylated micelles (62.3%) enhances micellar internalization into drugresistant MDA-MB-231 after 1h and magnetizes the cells after 6h than non-conjugated micelles. Immigration of MDA-MB-231 and 4T1 cells retards after 24h while significant reduction of mitochondrial membrane potential observed under hyperthermia. Intratumoral administration of nanomicelles in 4T1 orthotopic spontaneous metastasis model demonstrated anti-tumor and fibrosis mediated caging effect with simultaneous enhancement of MRI-T2 contrast.
Keywords: Hyperthermia, doxorubicin-SPION, chitosan micelle, breast cancer, theranostics, anti-integrin.
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Bioconjugate Chemistry
Introduction Breast cancer is the most leading cancer in women with 1.7 million new diagnoses contributing to 25% of all cancers in 2012 worldwide. The mortality rate of metastatic breast cancer is estimated to increase by 43% from 2015 to 2030 globally according to WHO report in 2015.1 Treatment of metastatic triple-negative breast cancer (PR-, ER-, HER-2- receptor) is still clinically an unmet challenge due to its lesser median time from relapse to death and lack of potential targets.2,3 Further, adverse non-specific toxicity caused by cytotoxic therapeutics demands the retraction of therapy.4 Use of drug delivery systems improves bioavailability by protecting the cargo from premature degradation as well as preventing premature interaction with biological environment. However, limitations such as diverse tumor vascularization and vessel porosity, poor cellular internalization of nanoparticles, lack of control over the drug release have been found to increase the incidence of multi-drug resistance (MDR), subsequently reduces the therapeutic efficacy of delivery systems.5,6 In addition, poor early diagnosis of patients with invasive breast cancer due to difficulty in diagnosing the tumor size of less than 5mm using current advanced clinical diagnostics namely mammogram, sonography, MRI, and PET leads to spontaneous metastasis in distant organs such as lung, bone, liver and brain.7–9 Thus a potential responsive delivery system in-built with the prognostics is the ultimatum for controlling the metastatic progression of breast cancer.
Super-paramagnetic iron oxide nanoparticles has been observed to be an excellent theranostic system in the detection of liver metastasis using MRI as compared to other eminent contrasting agent with concurrent benefit of adjuvant thermotherapy under alternating magnetic field.10 Though the hyperthermia exhibit anti-tumor activity by activating heat shock proteins to destruct the tumor tissues, thermotherapy has been combined with other therapies such as chemotherapy, radiotherapy to treat advanced stage of breast cancer. Superimposing of hyperthermia in chemotherapeutics escalates the efficacy of chemotherapy by reducing the 3 ACS Paragon Plus Environment
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adverse effects of both therapies. Though the drugs such as doxorubicin directly complexed with SPION via covalent interactions in many reports, electrostatic based complexation improves the pH sensitive drug release in addition to the magnetic drug targeting.11,12 Among various drug delivery systems, core-shell structures of amphipathic polymeric micelles are advantageous as it immobilizes hydrophobic drug in its core and hydrophilic shell imparts stability in circulation (
