Contents lists available at ScienceDirect Reactive and Functional Polymers journal homepage: www.elsevier.com/locate/react Vitamin-E/lipid based PEGylated polymeric micellar doxorubicin to sensitize doxorubicin-resistant cells towards treatment Omkara Swami Muddineti, Sri Vishnu Kiran Rompicharla, Preeti Kumari, Himanshu Bhatt, Balaram Ghosh, Swati Biswas ⁎ Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, Telangana, India ARTICLE INFO Keywords: Vitamin E PEG P-glycoprotein DOPE Multi-drug resistance ABSTRACT Multiple drug resistance (MDR) hampers therapeutic outcome of many anti-cancer drugs, including doxorubicin (Dox) by reducing their intracellular concentration at sub-therapeutic level. Vitamin-E/derivatives proved to sensitize cancer cells towards treatment by inhibiting MDR proteins. Here, previously synthesized α-tocopheryl succinate (α-TOS), poly(ethylene glycol) (PEG) and dioleoyl Phosphatidyl ethanolamine (DOPE) conjugated star shaped amphiphilic polymer, where three polymeric components were attached via lysine linker, was used to prepare micelles (VPM) to load the MDR-inducing chemotherapeutic agent, Doxorubicin. The micelles were subjected to physico-chemical characterizations, including hydrodynamic radius and polydispersity index (PDI) to assess formation of stable nanoparticles, zeta potential to measure the surface charge, encapsulation efficiency and drug loading to check effectivity of the nanocarrier system to carry the payload. Dox-loaded VPM (Dox- VPM) was evaluated in Dox resistant human colon carcinoma, SW 620-R and human breast adenocarcinoma, MDA MB-231-R cell lines. Dox-VPM demonstrated a particle size of 141.2 ± 0.78 nm with Dox-loading effi- ciency as 14.2 ± 0.19%. Time and concentration dependent cellular uptake was observed for Dox-VPM in both the cell lines. Dox-VPM exhibited significant cytotoxic action to both the resistant cancer cells. Dox-VPM ex- hibited superior therapeutic efficacy, which warrants further investigation of this nanomedicine in Dox-resistant cancers. 1. Introduction Chemotherapy is considered to be the mainstay of cancer treatment administered alone or in combination with two main anticancer treat- ment modalities, including radiation and surgery. However, treatment with majority of existing chemotherapeutic agents is limited by the development of multiple drug resistance in the treated cancer cells upon chronic drug administration, which is due to the over-expression of various ATP-binding cassette proteins as drug efflux transporters, including P-glycoproteins (P-gp), multiple drug resistant proteins (MRP1) and breast adenocarcinoma receptor protein (BCRP) [1,2]. Over-expression of P-gp on the cancer cell surface causes drug efflux from inside the cells causing reduction in cellular drug concentration to the sub-therapeutic level [3,4]. Various anticancer drugs, including anthracyclins such as doxorubicin (Dox), vinca alkaloids such as vin- cristine, taxanes such as paclitaxel, camptothecin such as topotecan, and miscellaneous drugs such as mitoxantrone, imatinib, methotrexate are P-gp substrates. So far, many P-gp inhibitors were reported such as α-tocopherol, pluronics, tween 80 and cremophor EL which act via various mechanisms that include inhibition of activity of ATPase en- zyme, change in membrane fluidity and reduced binding with the cell membrane by competitive inhibition of substrate [5,6]. Synergistic delivery of anticancer drug and P-gp inhibitor is a fa- vorable approach for the treatment of MDR cancer [7–9]. Various nano- formulation strategies have been reported such as polymer-drug con- jugates, micelles, phospholipid based liposomes and lipid based nano- particles for co-delivery of P-gp inhibitor and anti-cancer drugs, which demonstrated enhancement of therapeutic efficacy and less side effects of cancer chemotherapy [2,10–14]. Among all the nanocarriers, mi- celles showed promising results in inhibition of MDR owing to their small size, high stability, good biocompatibility, and flexible to modify with various targeting ligands [15]. Recently, vitamin-E based nanocarriers are being broadly in- vestigated and utilized in drug delivery owing to the several advantages associated with vitamin-E [2]. Incorporation of vitamin-E as one of the components in the drug delivery systems improves the hydrophobicity of the core resulting in higher drug loading and enhances the bio- compatibility of the carrier. Moreover, the great advantage comes from https://doi.org/10.1016/j.reactfunctpolym.2018.10.012 Received 22 September 2018; Received in revised form 26 October 2018; Accepted 27 October 2018 ⁎ Corresponding author. E-mail address: swati.biswas@hyderabad.bits-pilani.ac.in (S. Biswas). Reactive and Functional Polymers 134 (2019) 49–57 Available online 01 November 2018 1381-5148/ © 2018 Elsevier B.V. All rights reserved. T