A solid lipid nanoparticle formulation of 4-(N)-docosahexaenoyl 2′, 2′-difluorodeoxycytidine with increased solubility, stability, and antitumor activity

Solange A. Valdes, Riyad F. Alzhrani, Andres Rodriguez, Dharmika S.P. Lansakara-P, Sachin G. Thakkar, Zhengrong Cui

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Previously, we synthesized 4-(N)-docosahexaenoyl 2′, 2′-difluorodeoxycytidine (DHA-dFdC), a novel lipophilic compound with a potent, broad-spectrum antitumor activity. Herein, we report a solid lipid nanoparticle (SLN) formulation of DHA-dFdC with improved apparent aqueous solubility, chemical stability, as well as efficacy in a mouse model. The SLNs were prepared from lecithin/glycerol monostearate-in-water emulsions emulsified with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and Tween 20. The resultant DHA-dFdC-SLNs were 102.2 ± 7.3 nm in diameter and increased the apparent solubility of DHA-dFdC in water to at least 5.2 mg/mL, more than 200-fold higher than its intrinsic water solubility. DHA-dFdC in a lyophilized powder of DHA-dFdC-SLNs was significantly more stable than the waxy solid of pure DHA-dFdC. DHA-dFdC-SLNs also showed an increased cytotoxicity against certain tumor cells than DHA-dFdC. The plasma concentration of DHA-dFdC in mice intravenously injected with DHA-dFdC-SLNs in dispersion followed a bi-exponential model, with a half-life of ~44 h. In mice bearing B16-F10 murine melanoma, DHA-dFdC-SLNs were significantly more effective than DHA-dFdC in controlling the tumor growth. In addition, histology evaluation revealed a high level of apoptosis and tumor encapsulation in tumors in mice treated with DHA-dFdC-SLNs. DHA-dFdC-SLNs represents a new DHA-dFdC formulation with improved antitumor activity.

Original languageEnglish (US)
Article number118609
JournalInternational journal of pharmaceutics
Volume570
DOIs
StatePublished - Oct 30 2019

Fingerprint

Nanoparticles
Solubility
Lipids
Water
Neoplasms
Lecithins
Polysorbates
Emulsions
Powders
Glycerol
Half-Life
Melanoma
Histology
Apoptosis
Growth

Keywords

  • Antitumor activity
  • Cytotoxicity
  • Plasma pharmacokinetics
  • Solid lipid nanoparticles
  • Solubility
  • Stability

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

A solid lipid nanoparticle formulation of 4-(N)-docosahexaenoyl 2′, 2′-difluorodeoxycytidine with increased solubility, stability, and antitumor activity. / Valdes, Solange A.; Alzhrani, Riyad F.; Rodriguez, Andres; Lansakara-P, Dharmika S.P.; Thakkar, Sachin G.; Cui, Zhengrong.

In: International journal of pharmaceutics, Vol. 570, 118609, 30.10.2019.

Research output: Contribution to journalArticle

@article{f94f677338a349d780706213b1d931bf,
title = "A solid lipid nanoparticle formulation of 4-(N)-docosahexaenoyl 2′, 2′-difluorodeoxycytidine with increased solubility, stability, and antitumor activity",
abstract = "Previously, we synthesized 4-(N)-docosahexaenoyl 2′, 2′-difluorodeoxycytidine (DHA-dFdC), a novel lipophilic compound with a potent, broad-spectrum antitumor activity. Herein, we report a solid lipid nanoparticle (SLN) formulation of DHA-dFdC with improved apparent aqueous solubility, chemical stability, as well as efficacy in a mouse model. The SLNs were prepared from lecithin/glycerol monostearate-in-water emulsions emulsified with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and Tween 20. The resultant DHA-dFdC-SLNs were 102.2 ± 7.3 nm in diameter and increased the apparent solubility of DHA-dFdC in water to at least 5.2 mg/mL, more than 200-fold higher than its intrinsic water solubility. DHA-dFdC in a lyophilized powder of DHA-dFdC-SLNs was significantly more stable than the waxy solid of pure DHA-dFdC. DHA-dFdC-SLNs also showed an increased cytotoxicity against certain tumor cells than DHA-dFdC. The plasma concentration of DHA-dFdC in mice intravenously injected with DHA-dFdC-SLNs in dispersion followed a bi-exponential model, with a half-life of ~44 h. In mice bearing B16-F10 murine melanoma, DHA-dFdC-SLNs were significantly more effective than DHA-dFdC in controlling the tumor growth. In addition, histology evaluation revealed a high level of apoptosis and tumor encapsulation in tumors in mice treated with DHA-dFdC-SLNs. DHA-dFdC-SLNs represents a new DHA-dFdC formulation with improved antitumor activity.",
keywords = "Antitumor activity, Cytotoxicity, Plasma pharmacokinetics, Solid lipid nanoparticles, Solubility, Stability",
author = "Valdes, {Solange A.} and Alzhrani, {Riyad F.} and Andres Rodriguez and Lansakara-P, {Dharmika S.P.} and Thakkar, {Sachin G.} and Zhengrong Cui",
year = "2019",
month = "10",
day = "30",
doi = "10.1016/j.ijpharm.2019.118609",
language = "English (US)",
volume = "570",
journal = "International Journal of Pharmaceutics",
issn = "0378-5173",
publisher = "Elsevier",

}

TY - JOUR

T1 - A solid lipid nanoparticle formulation of 4-(N)-docosahexaenoyl 2′, 2′-difluorodeoxycytidine with increased solubility, stability, and antitumor activity

AU - Valdes, Solange A.

AU - Alzhrani, Riyad F.

AU - Rodriguez, Andres

AU - Lansakara-P, Dharmika S.P.

AU - Thakkar, Sachin G.

AU - Cui, Zhengrong

PY - 2019/10/30

Y1 - 2019/10/30

N2 - Previously, we synthesized 4-(N)-docosahexaenoyl 2′, 2′-difluorodeoxycytidine (DHA-dFdC), a novel lipophilic compound with a potent, broad-spectrum antitumor activity. Herein, we report a solid lipid nanoparticle (SLN) formulation of DHA-dFdC with improved apparent aqueous solubility, chemical stability, as well as efficacy in a mouse model. The SLNs were prepared from lecithin/glycerol monostearate-in-water emulsions emulsified with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and Tween 20. The resultant DHA-dFdC-SLNs were 102.2 ± 7.3 nm in diameter and increased the apparent solubility of DHA-dFdC in water to at least 5.2 mg/mL, more than 200-fold higher than its intrinsic water solubility. DHA-dFdC in a lyophilized powder of DHA-dFdC-SLNs was significantly more stable than the waxy solid of pure DHA-dFdC. DHA-dFdC-SLNs also showed an increased cytotoxicity against certain tumor cells than DHA-dFdC. The plasma concentration of DHA-dFdC in mice intravenously injected with DHA-dFdC-SLNs in dispersion followed a bi-exponential model, with a half-life of ~44 h. In mice bearing B16-F10 murine melanoma, DHA-dFdC-SLNs were significantly more effective than DHA-dFdC in controlling the tumor growth. In addition, histology evaluation revealed a high level of apoptosis and tumor encapsulation in tumors in mice treated with DHA-dFdC-SLNs. DHA-dFdC-SLNs represents a new DHA-dFdC formulation with improved antitumor activity.

AB - Previously, we synthesized 4-(N)-docosahexaenoyl 2′, 2′-difluorodeoxycytidine (DHA-dFdC), a novel lipophilic compound with a potent, broad-spectrum antitumor activity. Herein, we report a solid lipid nanoparticle (SLN) formulation of DHA-dFdC with improved apparent aqueous solubility, chemical stability, as well as efficacy in a mouse model. The SLNs were prepared from lecithin/glycerol monostearate-in-water emulsions emulsified with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and Tween 20. The resultant DHA-dFdC-SLNs were 102.2 ± 7.3 nm in diameter and increased the apparent solubility of DHA-dFdC in water to at least 5.2 mg/mL, more than 200-fold higher than its intrinsic water solubility. DHA-dFdC in a lyophilized powder of DHA-dFdC-SLNs was significantly more stable than the waxy solid of pure DHA-dFdC. DHA-dFdC-SLNs also showed an increased cytotoxicity against certain tumor cells than DHA-dFdC. The plasma concentration of DHA-dFdC in mice intravenously injected with DHA-dFdC-SLNs in dispersion followed a bi-exponential model, with a half-life of ~44 h. In mice bearing B16-F10 murine melanoma, DHA-dFdC-SLNs were significantly more effective than DHA-dFdC in controlling the tumor growth. In addition, histology evaluation revealed a high level of apoptosis and tumor encapsulation in tumors in mice treated with DHA-dFdC-SLNs. DHA-dFdC-SLNs represents a new DHA-dFdC formulation with improved antitumor activity.

KW - Antitumor activity

KW - Cytotoxicity

KW - Plasma pharmacokinetics

KW - Solid lipid nanoparticles

KW - Solubility

KW - Stability

UR - http://www.scopus.com/inward/record.url?scp=85071664584&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071664584&partnerID=8YFLogxK

U2 - 10.1016/j.ijpharm.2019.118609

DO - 10.1016/j.ijpharm.2019.118609

M3 - Article

C2 - 31415878

AN - SCOPUS:85071664584

VL - 570

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

SN - 0378-5173

M1 - 118609

ER -