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Nano-micellar Aggregates of Anticancer Cisplatin-Conjugated Poly(carboxylated 2-isopropenyl 2-oxazoline)-mPEG Copolymers

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Abstract

Cisplatin is an anticancer drug that can be used to treat a variety of solid tumors, where clinical use may be affected by several factors, including dose-limiting side effects and the emergence of drug resistance. Micellar-forming polymeric conjugates are a type of polymeric nanocarrier that can preferentially accumulate in tumors, thereby increasing therapeutic efficacy. In the current study, carboxylated PiPOx was synthesized first using a click reaction of 2-isopropenyl 2-oxazoline (iPOx) with thioglycolic acid (TGA) or methyl thioglycolate, followed by methyl triflate-initiated cationic ring opening polymerization (CROP). Next, different strategies were employed to prepare carboxylated PiPOx-mPEG copolymers: (a) CROP was initiated by iPOx-modified mPEG-thiol, (b) TGA-modified PiPOx were end-capped with mPEG-NH2, or (c) TGA-modified iPOx and iPOx-modified mPEG-thiol were randomly copolymerized. 1H-NMR, FT-IR, SEC, and potentiometric titration methods were used to characterize the synthesized polymers. Cisplatin-polymer conjugation was performed at three ratios of drug-to-polymer carboxyl groups (0.25, 0.5, and 1), and the conjugated cisplatin content was determined using UV–vis spectroscopy at 705 nm with O-phenylenediamine reagent. The cisplatin loading efficiencies (%) were 59.3, 26.7, and 91.0 for the respective copolymers at the chosen cisplatin/carboxyl 1:1 mol ratio. Cisplatin-conjugated PiPOx(TGA)-b-mPEG and mPEG-g-PiPOx(TGA) had mean hydrodynamic sizes of 113.3 and 178.8 nm, respectively. TEM imaging confirmed the formation of discrete and spherical particles of the cisplatin-conjugated copolymer. The MTT cytotoxicity assay demonstrated higher cytotoxicity of PiPOx(TGA)-b-mPEG compared to PiPOx(TGA)-g-mPEG polymers in both sensitive and resistant ovarian cancer cells. The IC50 values were approximately 113 µg/ml for PiPOx(TGA)-b-mPEG and 232 µg/ml for PiPOx(TGA)-g-mPEG in resistant tumor cells, confirming the potential application of cisplatin-conjugated copolymers in cancer chemotherapy.

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Abbreviations

A2780R:

A2780 cisplatin resistant

A2780S:

A2780 cisplatin sensitive

CROP:

Cationic ring opening polymerization

DIPEA, N:

N-diisopropylethylamine

DMF:

N,N-dimethylformamide

DMSO:

dimethyl sulfoxide

DTNB:

5,5-Dithio-bis-(2-nitrobenzoic acid)

EDTA:

Ethylenedinitrilotetraacetic acid

HEPES:

4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid)

iPOx:

2-Isopropenyl 2-oxazoline

mPEG:

Methoxy polyethylene glycol

MTG:

Methyl thioglycolate

PiPOx:

Poly (2-isopropenyl 2-oxazoline)

PiPOx(MTG):

Poly (2-isopropenyl 2-oxazoline)-methyl thioglycolate

PiPOx(TGA):

Poly (2-isopropenyl 2-oxazoline)-thioglycolic acid

Pox:

Poly-2-oxazoline

RPMI:

Roswell Park Memorial Institute

SEC:

Size exclusion chromatography

TEM:

Transmission electron microscopy

TGA:

Thioglycolic acid

THF:

Tetrahydrofuran

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Acknowledgements

The facility supports of “Center for Nanotechnology in Drug Delivery” are gratefully acknowledged.

Funding

This research has been financially supported by Shiraz University of Medical Sciences (SUMS) Grant No. 8988.

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Authors and Affiliations

  1. Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, 71345, Iran

    Zahra Sadat Hosseini Rezaei, Samira Sadat Abolmaali, Mohsen Salmanpour, Samaneh Mohammadi, Sedigheh Borandeh & Ali Mohammad Tamaddon

  2. Department of Pharmaceutical Nanotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, 71345, Iran

    Samira Sadat Abolmaali

  3. Cellular and Molecular Biology Research Center, Larestan University of Medical Sciences, Larestan, Iran

    Mohsen Salmanpour

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  1. Zahra Sadat Hosseini Rezaei
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Contributions

ZSHR: methodology, investigation, analysis, writing original draft; SSA: conceptualization, project administration, supervision, methodology, analysis, manuscript review and editing; MS: methodology, formal analysis, manuscript review and editing; SB: methodology, formal analysis, manuscript review and editing; SM, methodology, formal analysis, manuscript review and editing; AMT: conceptualization, methodology, manuscript review and editing.

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Correspondence to Samira Sadat Abolmaali or Ali Mohammad Tamaddon.

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Hosseini Rezaei, Z.S., Abolmaali, S.S., Salmanpour, M. et al. Nano-micellar Aggregates of Anticancer Cisplatin-Conjugated Poly(carboxylated 2-isopropenyl 2-oxazoline)-mPEG Copolymers. J Inorg Organomet Polym 34, 1121–1135 (2024). https://doi.org/10.1007/s10904-023-02877-5

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