The development, characterization and in vivo anti-ovarian cancer activity of poly(propylene imine) (PPI)-antibody conjugates containing encapsulated paclitaxel

doi:10.1016/j.nano.2014.09.006

Nanomedicine: Nanotechnology, Biology and Medicine

Volume 11, Issue 1, January 2015, Pages 207-218

https://doi.org/10.1016/j.nano.2014.09.006 Get rights and content

Abstract

Mesothelin, protein is frequently expressed in ovarian cancers. However, a full understanding of the biological functions of mesothelin is lacking. Here, we investigate the drug targeting potential of antibody conjugated modified half-generation poly (propylene imine) dendrimers i.e. immunodendrimers toward ovarian cancer with a model anti-cancer agent, paclitaxel (PTX). The synthesized plain 4.5G dendrimers as well as immunodendrimers were characterized by FT-IR, ¹H-NMR, TEM, and flow cytometry. Immunodendrimers exhibited considerably reduced hemolytic-, hepato- and nephrotoxicity. MTT cytotoxicity, flow cytometry and cell morphology studies were conducted in OVACAR-3 and A-431 cell. We demonstrate that PTX loaded immunodendrimers reduced the tumor volume significantly. The biodistribution studies further confirmed the targeting efficiency and higher biodistribution of immunodendrimers into the mesothelin protein expressing ovarian cancer cells. The results concluded that the developed immunodendrimers have potential to deliver significantly higher amount of the bioactive and have improved therapeutic outcome.

From the Clinical Editor

The authors investigated the drug targeting potential of antibody conjugated modified half-generation poly(propyleneimine) dendrimers toward ovarian cancer with a model anti-cancer agent, demonstrating delivery of significantly higher amount of paclitaxel (PTX) and improved therapeutic outcome.

Graphical abstract

The present investigation was aimed to develop and evaluate the anti-cancer potential of paclitaxel loaded poly(propylene imine) immunodendrimer. BALB/c mice were used as in vivo model for qualitative and quantitative assessment of toxicity, anti-cancer activity, and cancer targeting potential of immunodendrimer.

Section snippets

Materials

Paclitaxel (PTX) was received as gift sample from M/s Cipla (India). Primary antibody (mAbK1) and goat-anti-human secondary antibody were procured from Allied Scientific Products, Kolkata, India. Human epidermoid carcinoma cell line (A-431) and ovarian cancer cell line (OVCAR-3) were procured from National Centre for Cell Sciences, Pune, India. Details of other chemicals are provided in supplementary data.

Synthesis and characterization of 4.5G PPI dendrimers

Ethylene diamine (EDA) cored PPI dendrimers up to 4.5G (Figure 1, A) were synthesized by

Synthesis and characterization of 4.5G PPI dendrimers

PPI dendrimers up to 4.5G were synthesized as per the previously reported method.7, 21, 45 The synthesis of 0.5G PPI was confirmed by FT-IR spectroscopy. The various peaks obtained by FT-IR spectroscopy were analyzed and interpretated, which confirmed the synthesis of EDA-(CN)₄ (0.5G) by strong peak of nitrile at 2246.58 cm^− 1 and CH₂ bending at 1450.0 cm^− 1. Further the synthesis of 4.5G PPI dendrimers was confirmed by CH₂ rocking (796.7 cm^− 1), N single bond H bending (1597.0 cm^− 1), CH stretch (2957.5 cm^− 1), weak

Discussion

Ovarian cancer is highly prominent yet least explored area in global research efforts. Mesothelin protein is an attractive target for cancer therapy because of its differential cell surface associated expression in normal and tumor cells. In the present debut study we explored the anticancer potential of developed immunodendrimers exploiting the attribute of over-expression of mesothelin in ovarian cancer.

The EDA cored 4.5G PPI(–CN) dendrimer was synthesized and characterized by TEM, FT-IR, ¹

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Citation Excerpt :
Further, data from hemolytic, pharmacokinetic and biodistribution studies affirmed better targeting efficiency in mesothelin protein expressing ovarian neoplastic cells with reduced biodistribution and lowered toxicity in peripheral organs. Collectively, this report suggests the use of yet another immuno-dendrimer that could be used as nanocarrier to target ovarian cancer [102]. Cervical cancer is the fourth most general cancer types recorded amongst women.
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: Acknowledgments: The authors are obliged to All India Institute of Medical Sciences, New Delhi, India for providing TEM facility.

: Conflict of interest: The authors also report no conflict of interest related to this manuscript. One of the authors, Manoj S. Tare was financially supported by All India Council for Technical Education, New Delhi, India in terms of fellowship during the tenure of this work.

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Original ArticleThe development, characterization and in vivo anti-ovarian cancer activity of poly(propylene imine) (PPI)-antibody conjugates containing encapsulated paclitaxel

Abstract

From the Clinical Editor

Graphical abstract

Section snippets

Materials

Synthesis and characterization of 4.5G PPI dendrimers

Synthesis and characterization of 4.5G PPI dendrimers

Discussion

Prog Polym Sci

Int J Pharm

Int J Pharm

Curr Opin Pharmacol

Adv Drug Deliv Rev

Curr Opin Pharmacol

Anal Biochem

Methods Enzymol

Eur J Med Chem

Biomaterials

J Chromatogr B Biomed Sci Appl

J Immunol Methods

Biomaterials

J Pharm Biomed Anal

J Chromatogr

Int J Pharm

Int J Pharm

Biomaterials

J Control Release

Recent progress in the diagnosis and treatment of ovarian cancer

CA Cancer J Clin

Targeted drug delivery to macrophages

Expert Opin Drug Deliv

Surface-engineered dendrimers: a solution for toxicity issues

J Biomater Sci

Dendrimers in oncology: an expanding horizon

Chem Rev

Original Article
The development, characterization and in vivo anti-ovarian cancer activity of poly(propylene imine) (PPI)-antibody conjugates containing encapsulated paclitaxel