Self-assembled dual-drug loaded core-shell nanoparticles based on metal-free fully alternating polyester for cancer theranostics

Piyush Kumar Gupta; Sreenath Pappuru; Santosh Gupta; Bamadeb Patra; Debashis Chakraborty; Rama Shanker Verma

doi:10.1016/j.msec.2019.03.041

Self-assembled dual-drug loaded core-shell nanoparticles based on metal-free fully alternating polyester for cancer theranostics

Mater Sci Eng C Mater Biol Appl. 2019 Aug:101:448-463. doi: 10.1016/j.msec.2019.03.041. Epub 2019 Mar 12.

Authors

Piyush Kumar Gupta¹, Sreenath Pappuru², Santosh Gupta¹, Bamadeb Patra¹, Debashis Chakraborty³, Rama Shanker Verma⁴

Affiliations

¹ Stem Cell and Molecular Biology Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600036, Tamilnadu, India.
² Organometallic and Polymer Chemistry Laboratory, Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, Tamilnadu, India.
³ Organometallic and Polymer Chemistry Laboratory, Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, Tamilnadu, India. Electronic address: dchakraborty@iitm.ac.in.
⁴ Stem Cell and Molecular Biology Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600036, Tamilnadu, India. Electronic address: vermars@iitm.ac.in.

PMID: 31029340
DOI: 10.1016/j.msec.2019.03.041

Abstract

Recent research has been directed to the use of biocompatible and biodegradable metal-free fully alternating polyester nanomaterial in drug delivery application. The practice of triethyl borane (Et₃B)/Bis(triphenylphosphoranylidene)ammonium chloride (PPNCl) Lewis pair as non-metallic catalyst was carried out to synthesize alternating copolymer of commercially available tert-butyl glycidyl ether (tBGE) and phthalic anhydride (PA) (poly(tBGE-alt-PA) copolymer) of low M_nvia nearly controlled ring-opening copolymerization (ROCOP) reaction. This biocompatible, hemocompatible, and biodegradable copolymer was used in the fabrication of different nanodrug formulations (NDFs) loaded with doxorubicin (DOX), curcumin (CUR) and their combination. Transmission electron microscope (TEM) imaging showed the spherical shape and core-shell internal structure for all NDFs with an average particle diameter ranging between 200 and 250 nm. X-ray diffraction (XRD) analysis displayed the amorphous nature of both DOX and CUR after their entrapment into the copolymer matrix. Differential scanning colorimetry (DSC) analysis presented no potential chemical interactions between the drug and copolymer. The cellular drug uptake study showed the increased uptake for all NDFs compared to free drug and exhibited higher DOX and CUR accumulation in dual-drug loaded nanoparticles treated pancreatic cancer (MIA PaCa-2) cells. The in vitro drug release kinetic study displayed the slow sustained drug release behavior with anomalous transport for both DOX and CUR in a defined physiological environment. Further, the anti-tumor efficacy of all NDFs was examined on several different cancer cell lines and maximum cytotoxicity was observed in MIA PaCa-2 cells with low inhibitory concentration (IC₅₀) values. These NDFs inhibited the proliferation of MIA PaCa-2 cells due to cell cycle arrest in G2/M phase. In result, MIA PaCa-2 cells underwent apoptosis with significant changes in mitochondrial membrane potential and increased reactive oxygen species (ROS) level. In future, this study will open several novel insights related to the use of such biocompatible and biodegradable metal-free polyesters in targeted drug delivery, tissue engineering and other biomedical applications.

Keywords: Alternating copolymer; Cancer theranostics; Drug delivery; Lewis pair; Metal-free polyester.

MeSH terms

Calorimetry, Differential Scanning
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Curcumin / chemistry
Curcumin / pharmacology
Doxorubicin / chemistry
Doxorubicin / pharmacology
Drug Delivery Systems
Hep G2 Cells
Humans
Microscopy, Electron, Transmission
Nanoparticles / chemistry*
Nanoparticles / ultrastructure
Neoplasms / metabolism*
Polyesters / chemistry*
Reactive Oxygen Species / metabolism
Theranostic Nanomedicine / methods*
X-Ray Diffraction

Substances

Polyesters
Reactive Oxygen Species
Doxorubicin
Curcumin