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Multi-Reservoir Phospholipid Shell Encapsulating Protamine Nanocapsules for Co-Delivery of Letrozole and Celecoxib in Breast Cancer Therapy

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Abstract

Purpose

In the current work, we propose a combined delivery nanoplatform for letrozole (LTZ) and celecoxib (CXB).

Methods

Multi-reservoir nanocarriers were developed by enveloping protamine nanocapsules (PRM-NCs) within drug-phospholipid complex bilayer.

Results

Encapsulation of NCs within phospholipid bilayer was confirmed by both size increase from 109.7 to 179.8 nm and reduction of surface charge from +19.0 to +7.78 mV. The multi-compartmental core-shell structure enabled biphasic CXB release with initial fast release induced by complexation with phospholipid shell followed by prolonged release from oily core. Moreover, phospholipid coating provided protection for cationic PRM-NCs against interaction with RBCs and serum proteins enabling their systemic administration. Pharmacokinetic analysis demonstrated prolonged circulation and delayed clearance of both drugs after intravenous administration into rats. The superior anti-tumor efficacy of multi-reservoir NCs was manifested as powerful cytotoxicity against MCF-7 breast cancer cells and marked reduction in the mammary tumor volume in Ehrlich ascites bearing mice compared with free LTZ-CXB combination. Moreover, the NCs induced apoptotic caspase activation and marked inhibition of aromatase expression and angiogenic marker, VEGF as well as inhibition of both NFκB and TNFα.

Conclusions

Multi-reservoir phospholipid shell coating PRM-NCs could serve as a promising nanocarrier for parenteral combined delivery of LTZ and CXB.

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Abbreviations

AIs:

Aromatase inhibitors

CL:

Clearance

CXB:

Celecoxib

DMEM:

Dulbecco’s modified eagle medium

EAT:

Ehrlich ascites tumor

EE:

Encapsulation efficiency

FBS:

Fetal bovine serum

GEN:

Genistein

LTZ:

Letrozole

MRT0-inf :

Mean residence time

MTT:

3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide

NCs:

Nanocapsules

NF-κB:

Nuclear Factor Kappa-B

NPH:

Neutral protamine Hagedorn

PC:

Phosphatidylcholine

PCL:

Poly(Caprolactone)

PDI:

Polydispersityindex

PEG:

Poly(ethylene glycol)

PLGA:

Poly(lactic-co-glycolic acid)

PS:

Particle size

PRM:

Protamine

PTX:

Paclitaxel

PZI:

Protamine zinc insulin

RES:

Reticulo-endothelial system

SLS:

Sodium lauryl sulphate

TNF-α:

Tissue necrosis factor-alpha

VEGF:

Vascular endothelial growth factor

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Author information

Authors and Affiliations

  1. Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt

    Ahmed O. Elzoghby, Shaimaa K. Mostafa & Maged W. Helmy

  2. Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt

    Ahmed O. Elzoghby

  3. Department of Pharmaceutics, Faculty of Pharmacy and Drug Manufacturing, Pharos University, Alexandria, Egypt

    Shaimaa K. Mostafa

  4. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt

    Maged W. Helmy

  5. Pharmaceutical and Fermentation Industries Development Center (PFIDC), City for Scientific Research and Tehcnological Aplications (SRTA-City), New Borg El Arab, Alexandria, 21934, Egypt

    Maha A. ElDemellawy

  6. Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria, 21526, Egypt

    Salah A. Sheweita

Authors
  1. Ahmed O. Elzoghby
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  2. Shaimaa K. Mostafa
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Correspondence to Ahmed O. Elzoghby.

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Elzoghby, A.O., Mostafa, S.K., Helmy, M.W. et al. Multi-Reservoir Phospholipid Shell Encapsulating Protamine Nanocapsules for Co-Delivery of Letrozole and Celecoxib in Breast Cancer Therapy. Pharm Res 34, 1956–1969 (2017). https://doi.org/10.1007/s11095-017-2207-2

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  • DOI: https://doi.org/10.1007/s11095-017-2207-2

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