Abstract
Biotin receptors are overexpressed by various types of solid cancer cells and play a significant role in tumor metabolism, growth, and metastasis. Thus, targeting the biotin receptors on tumor cells may enhance the efficiency and reduce the side-effects of chemotherapy. The aim of this study was to develop a biotin-coupled poly(amido)amine (PAMAM) (PG4.5) dendrimer nanoparticle to enhance the tumor-specific delivery and intracellular uptake of anticancer drugs via receptor-mediated endocytosis. We modified PG4.5 with diethylenetriamine (DETA) followed by biotin via an amide bond and characterized the resulting PG4.5-DETA-biotin nanoparticles by 1H NMR, FTIR, and Raman spectroscopy. Loading and releasing of gemcitabine (GEM) from PG4.5-DETA-biotin were evaluated by UV–Visible spectrophotometry. Cell viability and cellular uptake were examined by MTT assay and flow cytometry to assess the biocompatibility, cellular internalization efficiency and antiproliferative activity of PG4.5-DETA-biotin/GEM. Gemcitabine-loaded PG4.5-DETA-biotin nanoparticles were spherical with a particle size of 81.6 ± 6.08 nm and zeta potential of 0.47 ± 1.25 mV. Maximum drug-loading content and encapsulation efficiency were 10.84 ± 0.16% and 47.01 ± 0.71%, respectively. Nearly 60.54 ± 1.99% and 73.96 ± 1.14% of gemcitabine was released from PG4.5-DETA-biotin/GEM nanoparticles after 48 h at the acidic pH values of 6.5 and 5, respectively. Flow cytometry and fluorescence microscopy of cellular uptake results revealed PG4.5-DETA-biotin/GEM nanoparticles selectively targeted cancer cells in vitro. Cytotoxicity assays demonstrated gemcitabine-loaded PG4.5-DETA-biotin significantly reduced cell viability and induced apoptosis in HeLa cells. Thus, biotin-coupled PG4.5-DETA nanocarrier could provide an effective, targeted drug delivery system and selectively convey gemcitabine into tumor cells.
Highlights
Cancer is a heterogeneous disease characterized by overexpression of oncogenes that lead to uncontrolled cell division [1]
Despite its low molecular weight and lipophobic nature, gemcitabine undergoes extensive first-pass metabolism and is rapidly deaminated in the blood, the plasma concentration of the drug drops below effective levels before passing through the whole body [9,10,11]
The biotin-targeted nanocarrier PG4.5-DETA-biotin was designed to achieve selective delivery of gemcitabine into cancer cells and synthesized via the two-step ethyl-N -(3-dimethylaminopropyl)carbodiimide (EDC)/NHS coupling reaction shown in Scheme 1
Summary
Cancer is a heterogeneous disease characterized by overexpression of oncogenes that lead to uncontrolled cell division [1]. Unlike other chemotherapeutic drugs to inhibit polymerase enzymes, gemcitabine can incorporate itself into DNA by replacing cytidine to trigger anti proliferative activity [4]. It is a deoxycytidine analogue of a gold-standard chemotherapeutic drug for unfit and elderly patient of advanced pancreatic, breast, lung, colon, bladder, cervical, and ovarian cancer [5,6]. Gemcitabine diffuses into the cell nucleus where it incorporates or binds to DNA polymerase and blocks the G1/S1 phase of the cell cycle and induces anti-proliferative effects and apoptosis [7,8]. Despite its low molecular weight and lipophobic nature, gemcitabine undergoes extensive first-pass metabolism and is rapidly deaminated in the blood, the plasma concentration of the drug drops below effective levels before passing through the whole body [9,10,11]
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