Antitumor activity of raloxifene-targeted poly(styrene maleic acid)-poly (amide-ether-ester-imide) co-polymeric nanomicelles loaded with docetaxel in breast cancer-bearing mice
Purpose Raloxifene (RA) receptors have over-expressed GPER-positive breast cancer tumors. The purpose of this work was to evaluate the antitumor activity and pharmacokinetic behavior of docetaxel (DTX), loaded in RA-targeted nanomicelles, which were designed to overcome a lack of specific distribution and inadequate DTX concentration in tumor tissues, as well as its cytotoxicity and damage to normal tissues. Methods DTX-loaded RA-targeted poly(styrene maleic acid) (SMA)- poly(amide-ether-esterimide)-poly(ethylene glycol) (PAEEI-PEG) nanomicelles were prepared; then, their antitumor activity and survival rate were studied in MC4-L2 tumors induced in BALB/c mice. The pharmacokinetics of DTX-loaded SMA-PAEEI-PEG-RA micelles was also investigated in comparison with free DTX. Results DTX-loaded SMA-PAEEI-PEG-RA micelles inhibited tumor growth considerably and increased animal survival as compared to free DTX and non-targeted micelles. SMA-PAEEIPEG-RA micelles enhanced significantly the area under the curve (AUC0-∞) 1.3 times as compared to free DTX and reduced clearance (CL) from 410.43 ml/kg.h (for free DTX) to 308.8 ml/kg.h (for SMA-PAEEI-PEG-RA micelles). Volume of distribution (Vdss) was also reduced 1.4 times as compared to free DTX. RA-targeted micelles increased tumor inhibition rate (TIR) 1.3 times and median survival time (MST) >1.5 times compared to free DTX. Percentage increase in life span (%ILS) was also enhanced significantly from 41.66% to >83.33% in MC4-L2 tumor-bearing BALB/c mice. Discussion All studies in this work showed the potential of DTX-loaded SMA-PAEEI-PEG-RA micelles in the treatment of GPER-positive receptor breast cancer tumors.
KeywordsPoly(styrene maleic acid) poly(amide-ether-ester-imide)-poly(ethylene glycol) targeted micelles raloxifene docetaxel
Financial support of the project by the Research Vice Chancellery of Isfahan University of Medical Sciences is appreciated. The authors gratefully appreciate the technical assistance of Dr. Mohajeri and MS Mahmoodi in doing immunohistochemical tests.
This study was funded by grant number 394283 of Isfahan University of Medical Sciences.
Compliance with ethical standards
Conflict of interest
Saeede Enteshari declares that she has no conflict of interest. Jaleh Varshosaz declares that she has no conflict of interest. Mohsen Minayian declares that he has no conflict of interest. Farshid Hassanzadeh declares that he has no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
- 11.Alexis F, Pridgen E, Molnar LK, Farokhzad OC (2000) Factors affecting the clearance and biodistribution of polymeric nanoparticles. Biotechnology 18:412–420Google Scholar
- 22.Varshosaz J, Enteshari S, Hassanzadeh F, Hashemi Bani B (2017) Synthesis of novel polystyrene-poly(amide-ether-ester-imide)-poly(ethylene glycol) co-polymeric micelles loaded with docetaxel: Physicochemical evaluation and cytotoxic effects on breast cancer cell lines. Mater Sci Mater Med (in press)Google Scholar
- 23.Varshosaz J, Enteshari S, Hassanzadeh F, Hashemi Bani B (2017) Raloxifene targeted styrene maleic acid (SMA)-poly ether ester imide–poly ethylene glycol (PAEEI-PEG) copolymeric micelles for the targeted delivery of docetaxel: Physicochemical evaluation and cytotoxic effects on breast cancer cell lines. Polos One (in press)Google Scholar
- 33.Rezazadeh M, Emami J, Hasanzadeh F, Sadeghi H, Minaiyan M, Mostafavi A, Rostami M, Lavasanifar A (2016) In vivo pharmacokinetics, biodistribution and anti-tumor effect of paclitaxel-loaded targeted chitosan-based polymeric micelle. Drug Deliv 23(5):1707–1717Google Scholar