Multifunctional nanoparticle–EpCAM aptamer bioconjugates: A paradigm for targeted drug delivery and imaging in cancer therapy

doi:10.1016/j.nano.2014.09.002

Nanomedicine: Nanotechnology, Biology and Medicine

Volume 11, Issue 2, February 2015, Pages 379-389

https://doi.org/10.1016/j.nano.2014.09.002 Get rights and content

Abstract

The promising proposition of multifunctional nanoparticles for cancer diagnostics and therapeutics has inspired the development of theranostic approach for improved cancer therapy. Moreover, active targeting of drug carrier to specific target site is crucial for providing efficient delivery of therapeutics and imaging agents. In this regard, the present study investigates the theranostic capabilities of nutlin-3a loaded poly (lactide-co-glycolide) nanoparticles, functionalized with a targeting ligand (EpCAM aptamer) and an imaging agent (quantum dots) for cancer therapy and bioimaging. A wide spectrum of in vitro analysis (cellular uptake study, cytotoxicity assay, cell cycle and apoptosis analysis, apoptosis associated proteins study) revealed superior therapeutic potentiality of targeted NPs over other formulations in EpCAM expressing cells. Moreover, our nanotheranostic system served as a superlative bio-imaging modality both in 2D monolayer culture and tumor spheroid model. Our result suggests that, these aptamer-guided multifunctional NPs may act as indispensable nanotheranostic approach toward cancer therapy.

From the Clinical Editor

This study investigated the theranostic capabilities of nutlin-3a loaded poly (lactide-co-glycolide) nanoparticles functionalized with a targeting ligand (EpCAM aptamer) and an imaging agent (quantum dots) for cancer therapy and bioimaging. It was concluded that the studied multifunctional targeted nanoparticle may become a viable and efficient approach in cancer therapy.

Graphical abstract

Schematic representation of multifunctional theranostic NPs for simultaneous cancer therapy and imaging.

Section snippets

Materials

Nutlin-3a was purchased from Cayman Chemical Company (Ann Arbor, MI, USA). Poly(d, l-lactide-co-glycolide) PLGA with a copolymer ratio of 50:50 and inherent viscosity (IV = 0.41) was obtained from Birmingham Polymers, Inc. (Birmingham, AL). All chemicals were obtained from Sigma–Aldrich Co. (St. Louis, MO) unless mentioned. All primary antibodies used were either obtained from Cell Signaling Technology, Inc. (Danvers, MA) or from Santa Cruz Biotechnology (Santa Cruz, CA). Secondary antibodies

Physiochemical characterization of drug loaded PLGA nanoparticles

Nutlin-3a loaded PLGA nanoparticles were formulated by emulsion-solvent evaporation method and result indicates that the formulated NPs are of nanometer size range with negative zeta potential (Figure 1, A, B and Table 1) and having smooth surface morphology (Figure 1, C). The EDC/NHS activation technique enables the conjugation of amine functional group of the Apt/QD with the carboxyl group of PLGA through the formation of an amide bond (Figure 1, D, E; Figures S1 and S2).27, 43 Further, the

Discussion

In spite of the ability of the contemporary chemotherapeutic treatment regimens to achieve relatively high rates of remission induction and survival, still there are challenges for successful cancer therapy. In this setting to overcome the challenges associated with cancer chemotherapy there has been progressively heightened interest in the development of a combinational approach for targeted drug delivery and controlled release technology which may pave the road to more effective yet safer

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: Conflict of interest: We do not have any conflict of interest.

: Manasi Das thanks the Council of Scientific Industrial Research, New Delhi, Government of India, for a Senior Research Fellowship.

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Original ArticleMultifunctional nanoparticle–EpCAM aptamer bioconjugates: A paradigm for targeted drug delivery and imaging in cancer therapy

Abstract

From the Clinical Editor

Graphical abstract

Section snippets

Materials

Physiochemical characterization of drug loaded PLGA nanoparticles

Discussion

Drug Discov Today

Biomaterials

Biochem Pharmacol

Eur J Cancer

Adv Drug Deliv Rev

Int J Pharm

Nano Today

Am J Pathol

J Control Release

J Biotechnol

Biomaterials

J Biomol Screen

J Control Release

Factors and mechanism of “EPR” effect and the enhanced antitumor effects of macromolecular drugs including SMANCS

Adv Exp Med Biol

Ligand-based targeted therapy for cancer tissue

Expert Opin Drug Deliv

Efficacy of transferrin-conjugated paclitaxel-loaded nanoparticles in a murine model of prostate cancer

Int J Cancer

Targeted magnetic iron oxide nanoparticles for tumor imaging and therapy

Int J Nanomedicine

In vivo activation of the p53 pathway by small-molecule antagonists of MDM2

Science

Recent advances in the therapeutic perspectives of Nutlin-3

Curr Pharm Des

HDM2 antagonist Nutlin-3 disrupts p73-HDM2 binding and enhances p73 function

Oncogene

Potent in vitro and in vivo antitumor effects of MDM2 inhibitor nutlin-3 in gastric cancer cells

Cancer Sci

Pharmacologic activation of p53 by small-molecule MDM2 antagonists

Curr Pharm Des

Reversal of P-glycoprotein-mediated multidrug resistance by the murine double minute 2 antagonist nutlin-3

Cancer Res

Nanoparticles loaded with Nutlin-3 display cytotoxicity towards p53(wild-type) JVM-2 but not towards p53(mutated) BJAB leukemic cells

Curr Med Chem

Nanoparticles engineered with rituximab and loaded with Nutlin-3 show promising therapeutic activity in B-leukemic xenografts

Clin Cancer Res

Original Article
Multifunctional nanoparticle–EpCAM aptamer bioconjugates: A paradigm for targeted drug delivery and imaging in cancer therapy