Bioreducible Cross-Linked Hyaluronic Acid/Calcium Phosphate Hybrid Nanoparticles for Specific Delivery of siRNA in Melanoma Tumor Therapy

Zhanwei Zhou, Huipeng Li, Kaikai Wang, Qian Guo, Chenzi Li, Hulin Jiang, Yiqiao Hu, David Oupicky, Minjie Sun

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

This study introduces a novel cross-linking strategy capable of successfully stabilizing CaP nanoparticles and stimuli-responsive small interfering RNA (siRNA) release. We synthesized a polysaccharide derivative thiolated hyaluronic acid (HA-SH), which was slightly modified but multifunctional and developed a smart redox-responsive delivery system. siRNA was efficaciously condensed by calcium phosphate (CaP) via electrostatic interaction to form a positively charged inner "core". Disulfide cross-linked HA (HA-ss-HA) was formed and played a role as an anionic outer "shell" to stabilize the CaP core. We demonstrated that the nanoparticles were stable both in the storage milieu and systemic circulation, thus overcoming the most serious disadvantage of CaP nanoparticles for gene delivery. Meanwhile, this smart system could selectively release siRNA into the cytosol by both a GSH-triggered disassembly and successful endosomal escape. Therefore, the hybrid delivery system achieved an 80% gene-silencing efficiency in vitro for both luciferase and Bcl2. Silencing of Bcl2 resulted in dramatic apoptosis of B16F10 cells. Besides, equipped with the tumor-targeting component HA, the nanoparticles significantly suppressed the growth of B16F10 xenograft tumor in mice. The anionic HA-ss-HA-equipped nanoparticles showed no apparent toxicity in vitro or in vivo, as well as showed a high transfection efficiency. Taken together, this redox-responsive, tumor-targeting smart anionic nanoparticle holds great promise for exploitation in functionalized siRNA delivery and tumor therapy.

Original languageEnglish (US)
Pages (from-to)14576-14589
Number of pages14
JournalACS Applied Materials and Interfaces
Volume9
Issue number17
DOIs
StatePublished - May 3 2017

Fingerprint

Hyaluronic acid
Calcium phosphate
Hyaluronic Acid
RNA
Small Interfering RNA
Tumors
Nanoparticles
Genes
Cell death
Polysaccharides
Coulomb interactions
Luciferases
Heterografts
Disulfides
Toxicity
monobasic calcium phosphate
Apoptosis
Derivatives
calcium phosphate

Keywords

  • antitumor
  • calcium phosphate
  • hyaluronic acid
  • hybrid nanoparticles
  • redox responsive
  • siRNA delivery

ASJC Scopus subject areas

  • Materials Science(all)

Cite this

Bioreducible Cross-Linked Hyaluronic Acid/Calcium Phosphate Hybrid Nanoparticles for Specific Delivery of siRNA in Melanoma Tumor Therapy. / Zhou, Zhanwei; Li, Huipeng; Wang, Kaikai; Guo, Qian; Li, Chenzi; Jiang, Hulin; Hu, Yiqiao; Oupicky, David; Sun, Minjie.

In: ACS Applied Materials and Interfaces, Vol. 9, No. 17, 03.05.2017, p. 14576-14589.

Research output: Contribution to journalArticle

Zhou, Zhanwei ; Li, Huipeng ; Wang, Kaikai ; Guo, Qian ; Li, Chenzi ; Jiang, Hulin ; Hu, Yiqiao ; Oupicky, David ; Sun, Minjie. / Bioreducible Cross-Linked Hyaluronic Acid/Calcium Phosphate Hybrid Nanoparticles for Specific Delivery of siRNA in Melanoma Tumor Therapy. In: ACS Applied Materials and Interfaces. 2017 ; Vol. 9, No. 17. pp. 14576-14589.
@article{b1d325f97cd741969a621811b3beaa2a,
title = "Bioreducible Cross-Linked Hyaluronic Acid/Calcium Phosphate Hybrid Nanoparticles for Specific Delivery of siRNA in Melanoma Tumor Therapy",
abstract = "This study introduces a novel cross-linking strategy capable of successfully stabilizing CaP nanoparticles and stimuli-responsive small interfering RNA (siRNA) release. We synthesized a polysaccharide derivative thiolated hyaluronic acid (HA-SH), which was slightly modified but multifunctional and developed a smart redox-responsive delivery system. siRNA was efficaciously condensed by calcium phosphate (CaP) via electrostatic interaction to form a positively charged inner {"}core{"}. Disulfide cross-linked HA (HA-ss-HA) was formed and played a role as an anionic outer {"}shell{"} to stabilize the CaP core. We demonstrated that the nanoparticles were stable both in the storage milieu and systemic circulation, thus overcoming the most serious disadvantage of CaP nanoparticles for gene delivery. Meanwhile, this smart system could selectively release siRNA into the cytosol by both a GSH-triggered disassembly and successful endosomal escape. Therefore, the hybrid delivery system achieved an 80{\%} gene-silencing efficiency in vitro for both luciferase and Bcl2. Silencing of Bcl2 resulted in dramatic apoptosis of B16F10 cells. Besides, equipped with the tumor-targeting component HA, the nanoparticles significantly suppressed the growth of B16F10 xenograft tumor in mice. The anionic HA-ss-HA-equipped nanoparticles showed no apparent toxicity in vitro or in vivo, as well as showed a high transfection efficiency. Taken together, this redox-responsive, tumor-targeting smart anionic nanoparticle holds great promise for exploitation in functionalized siRNA delivery and tumor therapy.",
keywords = "antitumor, calcium phosphate, hyaluronic acid, hybrid nanoparticles, redox responsive, siRNA delivery",
author = "Zhanwei Zhou and Huipeng Li and Kaikai Wang and Qian Guo and Chenzi Li and Hulin Jiang and Yiqiao Hu and David Oupicky and Minjie Sun",
year = "2017",
month = "5",
day = "3",
doi = "10.1021/acsami.6b15347",
language = "English (US)",
volume = "9",
pages = "14576--14589",
journal = "ACS applied materials & interfaces",
issn = "1944-8244",
publisher = "American Chemical Society",
number = "17",

}

TY - JOUR

T1 - Bioreducible Cross-Linked Hyaluronic Acid/Calcium Phosphate Hybrid Nanoparticles for Specific Delivery of siRNA in Melanoma Tumor Therapy

AU - Zhou, Zhanwei

AU - Li, Huipeng

AU - Wang, Kaikai

AU - Guo, Qian

AU - Li, Chenzi

AU - Jiang, Hulin

AU - Hu, Yiqiao

AU - Oupicky, David

AU - Sun, Minjie

PY - 2017/5/3

Y1 - 2017/5/3

N2 - This study introduces a novel cross-linking strategy capable of successfully stabilizing CaP nanoparticles and stimuli-responsive small interfering RNA (siRNA) release. We synthesized a polysaccharide derivative thiolated hyaluronic acid (HA-SH), which was slightly modified but multifunctional and developed a smart redox-responsive delivery system. siRNA was efficaciously condensed by calcium phosphate (CaP) via electrostatic interaction to form a positively charged inner "core". Disulfide cross-linked HA (HA-ss-HA) was formed and played a role as an anionic outer "shell" to stabilize the CaP core. We demonstrated that the nanoparticles were stable both in the storage milieu and systemic circulation, thus overcoming the most serious disadvantage of CaP nanoparticles for gene delivery. Meanwhile, this smart system could selectively release siRNA into the cytosol by both a GSH-triggered disassembly and successful endosomal escape. Therefore, the hybrid delivery system achieved an 80% gene-silencing efficiency in vitro for both luciferase and Bcl2. Silencing of Bcl2 resulted in dramatic apoptosis of B16F10 cells. Besides, equipped with the tumor-targeting component HA, the nanoparticles significantly suppressed the growth of B16F10 xenograft tumor in mice. The anionic HA-ss-HA-equipped nanoparticles showed no apparent toxicity in vitro or in vivo, as well as showed a high transfection efficiency. Taken together, this redox-responsive, tumor-targeting smart anionic nanoparticle holds great promise for exploitation in functionalized siRNA delivery and tumor therapy.

AB - This study introduces a novel cross-linking strategy capable of successfully stabilizing CaP nanoparticles and stimuli-responsive small interfering RNA (siRNA) release. We synthesized a polysaccharide derivative thiolated hyaluronic acid (HA-SH), which was slightly modified but multifunctional and developed a smart redox-responsive delivery system. siRNA was efficaciously condensed by calcium phosphate (CaP) via electrostatic interaction to form a positively charged inner "core". Disulfide cross-linked HA (HA-ss-HA) was formed and played a role as an anionic outer "shell" to stabilize the CaP core. We demonstrated that the nanoparticles were stable both in the storage milieu and systemic circulation, thus overcoming the most serious disadvantage of CaP nanoparticles for gene delivery. Meanwhile, this smart system could selectively release siRNA into the cytosol by both a GSH-triggered disassembly and successful endosomal escape. Therefore, the hybrid delivery system achieved an 80% gene-silencing efficiency in vitro for both luciferase and Bcl2. Silencing of Bcl2 resulted in dramatic apoptosis of B16F10 cells. Besides, equipped with the tumor-targeting component HA, the nanoparticles significantly suppressed the growth of B16F10 xenograft tumor in mice. The anionic HA-ss-HA-equipped nanoparticles showed no apparent toxicity in vitro or in vivo, as well as showed a high transfection efficiency. Taken together, this redox-responsive, tumor-targeting smart anionic nanoparticle holds great promise for exploitation in functionalized siRNA delivery and tumor therapy.

KW - antitumor

KW - calcium phosphate

KW - hyaluronic acid

KW - hybrid nanoparticles

KW - redox responsive

KW - siRNA delivery

UR - http://www.scopus.com/inward/record.url?scp=85018982957&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85018982957&partnerID=8YFLogxK

U2 - 10.1021/acsami.6b15347

DO - 10.1021/acsami.6b15347

M3 - Article

C2 - 28393529

AN - SCOPUS:85018982957

VL - 9

SP - 14576

EP - 14589

JO - ACS applied materials & interfaces

JF - ACS applied materials & interfaces

SN - 1944-8244

IS - 17

ER -