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Nano-Co-Delivery of Berberine and Anticancer Drug Using PLGA Nanoparticles: Exploration of Better Anticancer Activity and In Vivo Kinetics

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Abstract

Purpose

Combinatorial approach can be beneficial for cancer treatment with better patient recovery. Co-delivery of natural and synthetic anticancer drug not only valuable to achieve better anticancer effectivity but also to ascertain toxicity. This study was aimed to co-deliver berberine (natural origin) and doxorubicin (synthetic origin) utilizing conjugation/encapsulation strategy through poly (lactic-co-glycolic acid) (PLGA) nanoparticles.

Methods

Doxorubicin was efficiently conjugated to PLGA via carbodiimide chemistry and the PLGA-doxorubicin conjugate (PDC) was used for encapsulation of berberine (PDBNP).

Results

Significant anti-proliferative against MDA-MB-231 and T47D breast cancer cell lines were observed with IC50 of 1.94 ± 0.22 and 1.02 ± 0.36 μM, which was significantly better than both the bio-actives (p < 0.05). The ROS study revealed that the PDBNP portrayed the slight increase in the reactive oxygen species (ROS) pattern in MDA-MB-231 cell line in a dose-dependent manner, while in T47D cells, no significant change in ROS was seen. PDBNP exhibits significant alteration (depolarization) in mitochondrial membrane permeability and arrest of cell cycle progression at sub G1 phase while the Annexin V/PI assay followed by confocal microscopy resulted into cell death mode to be because of necrosis against MDA-MB-231 cells. In vivo studies in Sprague Dawley rats revealed almost 14-fold increase in half life and a significant increase in plasma drug concentration.

Conclusion

The overall approach of PLGA based co-delivery of doxorubicin and berberine witnessed synergetic effect and reduced toxicity as evidenced by preliminary toxicity studies.

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Abbreviations

AFM:

Atomic force microscopy

DCM:

Dichloromethane

EDC:

1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide

hPBMCs:

Human Peripheral Blood Mononuclear Cells

NHS:

N-hydroxy succinimide

PDBNP:

Berberine loaded PLGA-doxorubicin nanoparticles

PDC:

PLGA-doxorubicin conjugate

PLGA:

Poly lactide-co-glycolide

PNP:

Blank nanoparticle

PVA:

Polyvinyl alcohol

RBCs:

Red blood cells

ROS:

Reactive oxygen species

SEM:

Scanning electron microscopy

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to acknowledge the financial support received from Department of Science and Technology and University Grants Commission, New Delhi, India to Dr. Umesh Gupta in the form of DST Start up Research Grant (for Young Scientists). The first author (IK) also would like to acknowledge Indian Council of Medical Research (ICMR), New Delhi (Award letter no. 45/12/2018-Nan/BMS) for providing Senior Research Fellowship (SRF). GJ thanks CSIR, New Delhi (Grant no. 05/1051(0011)/2018-EMR-I) for providing SRF. The authors declare no competing financial interest. The authors would also like to acknowledge the Central Instrumentation Laboraory Central University of Punjab for extending facilities to carry out microscopy.

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Authors and Affiliations

  1. Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandarsindri, Ajmer, Rajasthan, 305817, India

    Iliyas Khan & Umesh Gupta

  2. Department of Pharmaceutical Sciences and Natural Products, School of Basic and Applied Sciences, Central University of Punjab, Bathinda, 151001, India

    Gaurav Joshi & Raj Kumar

  3. Rungta College of Pharmaceutical Science and Research, Kohka, Bhilai, Chhattisgarh, 490024, India

    Kartik T Nakhate &  Ajazuddin

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  1. Iliyas Khan
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  2. Gaurav Joshi
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  4. Ajazuddin
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Correspondence to Umesh Gupta.

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Khan, I., Joshi, G., Nakhate, K.T. et al. Nano-Co-Delivery of Berberine and Anticancer Drug Using PLGA Nanoparticles: Exploration of Better Anticancer Activity and In Vivo Kinetics. Pharm Res 36, 149 (2019). https://doi.org/10.1007/s11095-019-2677-5

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  • DOI: https://doi.org/10.1007/s11095-019-2677-5

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