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Quality by design approach-based fabrication and evaluation of self-nanoemulsifying drug delivery system for improved delivery of venetoclax

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Abstract

Breast cancer is reported as one of the most prevalent non-cutaneous malignancies in women. Venetoclax (VEN) is an approved BCl-2 inhibitor for the treatment of chronic myeloid leukemia with very limited oral bioavailability and exhibits an enormous impact on breast cancer. In the current investigation, venetoclax-loaded self-nanoemulsifying drug delivery systems (VEN-SNEDDS) were designed and fabricated to improve the aqueous solubility, permeability, and anticancer efficacy of VEN. Various surface-active parameters of the reconstituted SNEDDS were determined to scrutinize the performance of the selected surfactant mixture. Central composite design (CCD) was used to optimize the VEN-SNEDDS. The globule size of reconstituted VEN-SNEDDS was 71.3 ± 2.8 nm with a polydispersity index of 0.113 ± 0.01. VEN-SNEDDS displayed approximately 3–4 fold, 6–7 fold, and 5–6 fold reduced IC50 as compared to free VEN in MDA-MB-231, MCF-7, and T47 D cells, respectively. VEN-SNEDDS showed greater cellular uptake, apoptosis, reactive oxygen species generation, and higher BAX/BCL2 ratio with decreased caspase 3 and 8 and BCL-2 levels in the MDA-MB-231 cells compared to pure VEN. VEN-SNEDDS exhibited approximately fivefold enhancement in Cmax and an improved oral bioavailability compared to VEN suspension in in vivo pharmacokinetic studies.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding authors on reasonable request.

Abbreviations

AO/EB:

Acridine orange/ethidium bromide

ATCC:

American Type Culture Collection

BCL-2:

B-cell lymphoma 2

BCS:

Biopharmaceutical classification system

CCD:

Central composite design

CLL:

Chronic lymphocytic leukemia

DCFDA:

2′,7′-Dichlorofluorescein diacetate

DMSO:

Dimethyl sulfoxide

DoE:

Design of experiments

DAPI:

4′,6-Diamidino-2-phenylindole

EE:

Emulsification efficiency

EPR:

Enhanced permeability retention

FBS:

Fetal bovine serum

GIT:

Gastrointestinal tract

HCl:

Hydrochloric acid

HLB:

Hydrophilic-lipophilic balance

IC50 :

Inhibitory concentration

IFT:

Interfacial tension

mN/m:

Millinewtons/meter

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NCCS:

National Centre for Cell Sciences

o/w:

Oil in water

PARP:

Poly (ADP-ribose) polymerase

P-gp:

P glycoprotein

PVDF:

Polyvinylidene fluoride

ROS:

Reactive oxygen species

RP-HPLC:

Reverse-phase high-performance liquid chromatography

RPMI:

Roswell Park Memorial Institute

SNEDDS:

Self-nanoemulsifying drug delivery system

SFT:

Surface tension

S mix :

Surfactant mixture

TEM:

Transmission electron microscopy

VEN:

Venetoclax

VEN-SNEDDS:

Venetoclax-loaded SNEDDS

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Acknowledgements

The authors would like to acknowledge the Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad (Ministry of Chemical and Fertilizers, India), for providing extending facilities during this manuscript (Manuscript communication no.: NIPER-H/2023-).

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  1. Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India

    Naveen Rajana, Padakanti Sandeep Chary, Yeruva Sri Pooja, Valamla Bhavana & Neelesh Kumar Mehra

  2. Department of Biological Science, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India

    Hoshiyar Singh, Santosh Kumar Guru & Shashi Bala Singh

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Rajana, N., Chary, P.S., Pooja, Y.S. et al. Quality by design approach-based fabrication and evaluation of self-nanoemulsifying drug delivery system for improved delivery of venetoclax. Drug Deliv. and Transl. Res. 14, 1277–1300 (2024). https://doi.org/10.1007/s13346-023-01462-0

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