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    Contents lists available at ScienceDirect
    International Journal of Pharmaceutics
    journal homepage:
    Biotin functionalized PEGylated poly(amidoamine) dendrimer conjugate for T active targeting of paclitaxel in cancer
    Sri Vishnu Kiran Rompicharla, Preeti Kumari, Himanshu Bhatt, Balaram Ghosh, Swati Biswas
    Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Medchal, Hyderabad, Telangana 500078, India
    PAMAM dendrimers
    Active targeting
    In the current study, we employed poly(amidoamine) (PAMAM) dendrimers of generation 4 (G4) to deliver paclitaxel (PTX), a poorly soluble anti-cancer agent precisely to cancer 1793052-96-6 via its conjugation on dendrimer surface. Further, G4 PAMAM has been PEGylated (PEG) and tagged with Biotin, an essential micronutrient for cellular functions, receptors of which are overexpressed in certain cancers. The synthesized multifunctional conjugates were characterized by 1H NMR and zeta potential analysis techniques. In addition, the conjugates were evaluated in vitro in cell monolayers and 3D spheroids of biotin receptor over-expressed A549 cell line (human non-small cell lung cancer). G4 PTX PEG-Biotin conjugate penetrated at significantly higher extent in monolayers as well as spheroids as studied by flow cytometry and confocal microscopy by visualizing the cells at varied depth. The G4 PTX PEG-Biotin conjugate demonstrated higher cytotoxicity compared to free PTX and G4 PTX PEG conjugate as assessed by MTT assay in monolayers and Presto Blue assay in detached spheroidal cells. G4 PTX PEG-Biotin demonstrated significant inhibition of growth of tumor spheroids. Therefore, the newly synthesized biotin anchored PTX-conjugated dendrimer system is promising and could be further explored for efficiently delivering PTX to biotin receptor overexpressed cancers.
    1. Introduction
    Cancer is a leading cause of death worldwide. Chemotherapy, the first line of treatment, poses deleterious effect on the normal cells in a patient’s body making it a primary obstacle to the clinical application of otherwise potent anticancer drugs (Tripodo et al., 2014). The efficacy and tolerability of anticancer agents can be increased by employing target specific drug delivery systems (DDS) that can limit the associated side effects and improve treatment prognosis (Ren et al., 2015). Several potent chemotherapeutic agents like taxols, epirubicin, platinum com-pounds, methotrexate, doxorubicin (DOX) etc., are clinically used for a variety of cancer treatments. However, most of the chemotherapies are 1793052-96-6 conventional, and therefore, pose significant adverse effects (Abraham et al., 2005; Celik et al., 2013; Šimůnek et al., 2009; Yao et al., 2007). Therefore, DDS with targeting moieties that specifically target cancer cells could be a promising treatment strategy to overcome such short-
    Nanocarriers, by virtue of their size, leaky vasculatures in tumor and poor lymphatic clearance get accumulated to the tumor micro-environment via the phenomenon, commonly known as Enhanced Permeability and Retention (EPR) effect. However, a successful cancer treatment wherein sufficient amount of drug has to reach the site of action cannot solely rely on EPR or passive targeting. Cancer cells need more micronutrients than normal cells for their proliferation and sur-vival. As a consequence, they have overexpression of certain receptors which can be actively targeted using specific ligands (Russell-Jones et al., 2004). Different ligands, including proteins, hormones, vitamins, and growth factors which are identified by cancer cells for their active internalization, are attached to the backbone of the DDSkk (Nateghian et al., 2016). If the circulation times are long enough, effective trans-port to the site of action and substantial uptake of drug via endocytosis
    Corresponding author at: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Medchal, Hyderabad, Telangana 500078, India. E-mail address: [email protected] (S. Biswas).
    Available online 29 December 2018
    S.V.K. Rompicharla et al.