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Author: search.filters.author.Roy, AniruddhaSubject: search.filters.subject.Docetaxel

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    Recent progress in the development of polysaccharide conjugates of docetaxel and paclitaxel
    (Wiley, 2014-03) Roy, Aniruddha
    Taxanes are one of the most potent and broadest spectrum chemotherapeutics used clinically, but also induce significant side effects. Different strategies have been developed to produce a safer taxane formulation. Development of polysaccharide drug conjugates has increased in the recent years because of the demonstrated biocompatibility, biodegradability, safety, and low cost of the biopolymers. This review focuses on polysaccharide–taxane conjugates and provides an overview on various conjugation strategies and their effect on the efficacy. Detailed analyses on the designing factors of an effective polysaccharide–drug conjugate are provided with a discussion on the future direction of this field.
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    Carboxymethylcellulose-Based and Docetaxel-Loaded Nanoparticles Circumvent P-Glycoprotein-Mediated Multidrug Resistance
    (ACS, 2014-02) Roy, Aniruddha
    Taxanes are a class of anticancer agents with a broad spectrum and have been widely used to treat a variety of cancer. However, its long-term use has been hampered by accumulating toxicity and development of drug resistance. The most extensively reported mechanism of resistance is the overexpression of P-glycoprotein (Pgp). We have developed a PEGylated carboxymethylcellulose conjugate of docetaxel (Cellax), which condenses into ∼120 nm nanoparticles. Here we demonstrated that Cellax therapy did not upregulate Pgp expression in MDA-MB-231 and EMT-6 breast tumor cells, whereas a significant increase in Pgp expression was measured with native docetaxel (DTX) treatment. Treatment with DTX led to 4–7-fold higher Pgp mRNA expression and 2-fold higher Pgp protein expression compared with Cellax treatment in the in vitro and in vivo system, respectively. Cellax also exhibited significantly increased efficacy compared with that of DTX in a taxane-resistant breast tumor model. Against the highly Pgp expressing EMT6/AR1 cells, Cellax exhibited a 6.5 times lower IC50 compared with that of native DTX, and in the in vivo model, Cellax exhibited 90% tumor growth inhibition, while native DTX had no significant antitumor activity.
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    Docetaxel-carboxymethylcellulose nanoparticles target cells via a SPARC and albumin dependent mechanism
    (Elsevier, 2015-08) Roy, Aniruddha
    Cellax, a polymer-docetaxel (DTX) conjugate that self-assembled into 120 nm particles, displayed significant enhancements in safety and efficacy over native DTX across a number of primary and metastatic tumor models. Despite these exciting preclinical data, the underlying mechanism of delivery of Cellax remains elusive. Herein, we demonstrated that serum albumin efficiently adsorbed onto the Cellax particles with a 4-fold increased avidity compared to native DTX, and the uptake of Cellax by cells was primarily driven by an albumin and SPARC (secreted protein acidic and rich in cysteine, an albumin binder) dependent internalization mechanism. In the SPARC-positive cells, a >2-fold increase in cellular internalization of Cellax was observed in the presence of albumin. In the SPARC-negative cells, no difference in Cellax internalization was observed in the presence or absence of albumin. Evaluation of the internalization mechanism using endocytotic inhibitors revealed that Cellax was internalized predominantly via a clathrin-mediated endocytotic mechanism. Upon internalization, it was demonstrated that Cellax was entrapped within the endo-lysosomal and autophagosomal compartments. Analysis of the tumor SPARC level with tumor growth inhibition of Cellax in a panel of tumor models revealed a positive and linear correlation (R2 > 0.9). Thus, this albumin and SPARC-dependent pathway for Cellax delivery to tumors was confirmed both in vitro and in vivo.
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    Overcoming drug resistance with a docetaxel and disulfiram loaded pH-sensitive nanoparticle
    (Elsevier, 2023-04) Roy, Aniruddha
    Previous studies have demonstrated that breast cancer cells deploy a myriad array of strategies to thwart the activity of anticancer drugs like docetaxel (DTX), including acquired drug resistance due to overexpression of drug-efflux pumps like P-glycoprotein (P-gp) and innate drug resistance by cancer stem cells (CSCs). As disulfiram (DSF) can inhibit both P-gp and CSCs, we hypothesized that co-treatment of DTX and DSF could sensitize the drug-resistant breast cancer cells. To deliver a fixed dose ratio of DTX and DSF targeted to the tumor, a tumor extracellular pH-responsive nanoparticle (NP) was developed using a histidine-conjugated star-shaped PLGA with TPGS surface decoration ([DD]NpH-T). By releasing the encapsulated drugs in the tumor microenvironment, pH-sensitive NPs can overcome the tumor stroma-based resistance against nanomedicines. In in-vitro studies, [DD]NpH-T exhibited increased drug release at pH 6.8, improved penetration in a 3D tumor spheroid, reduced serum protein adsorption, and enhanced cytotoxic efficacy against both innate and acquired DTX-resistant breast cancer cells. In in-vivo studies, a significant increase in plasma AUC and tumor drug delivery was observed with [DD]NpH-T, which resulted in an enhanced in-vivo anti-tumor efficacy against a mouse orthotopic breast cancer, with a significantly increased intratumoral ROS and apoptosis, while decreasing P-gp expression and prevention of lung metastasis. Altogether, the current study demonstrated that the DTX and DSF combination could effectively target multiple drug-resistance pathways in-vitro, and the in-vivo delivery of this drug combination using TPGS-decorated pH-sensitive NPs could increase tumor accumulation, resulting in improved anti-tumor efficacy.
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    Development of a tumor extracellular pH-responsive nanocarrier by terminal histidine conjugation in a star shaped poly(lactic-co-glycolic acid)
    (Elsiever, 2021) Chowdhury, Rajdeep; Roy, Aniruddha
    After reaching the tumor site, nanoparticles (NPs) mostly accumulate in the periphery of the tumor, as their intra-tumoral penetration is prevented due to the low perfusion, high interstitial fluid pressure, and dense matrix present in the tumor. A pH-responsive carrier can improve tumor permeation by releasing the drug quickly in the acidic tumor pH, helping its uniform tumor distribution through diffusion. In the current study, we have developed a histidine modified star-shaped PLGA (sPLGA-His) for the tumor-targeted delivery of the drug combination of docetaxel and disulfiram. The sPLGA-His NPs exhibited a rapid pH-responsive drug release behavior, with significantly increased drug release at pH 6.5 compared to pH 7.4 in 12 h. In-vitro cytotoxicity analysis showed that the pH-sensitive sPLGA-His NPs had enhanced efficacy in both 2D and 3D cell culture models. In the cell uptake study, the sPLGA-His NPs exhibited endosomal escape and uniform cellular distribution, whereas sPLGA NPs were found to be accumulated in the endosomes. In the tumor spheroid model, deep penetration was observed with the sPLGA-His NPs, while sPLGA NPs were found to be accumulated in the periphery. Using fluorescent colocalization as well as FRET analysis, increased release of the encapsulated cargo was noticed with the sPLGA-His NPs, compared to sPLGA NPs. Altogether, the sPLGA-His NPs can be used as a tumor extracellular pH-responsive nanocarrier for efficient drug delivery to the tumor.