Extremely long tumor retention, multi-responsive boronate crosslinked micelles with superior therapeutic efficacy for ovarian cancer

Wenwu Xiao, Nell Suby, Kai Xiao, Tzu-Yin Lin, Nasir Al Awwad, Kit Lam, Yuanpei Li

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Mortality rates for ovarian cancer have declined only slightly in the past forty years since the “War on Cancer” was declared. The current standard care of ovarian cancer is still cytoredutive surgery followed by several cycles of chemotherapy. The severe adverse effect from chemotherapy drug is a leading cause for the patients to fail in long term therapy post-surgery. New nanocarriers able to minimize the premature drug release in blood circulation while releasing drug on-demand at tumor site have profound impact on the improvement of the efficacy and toxicity profile of the chemotherapeutic drugs. Here we reported a unique type of extremely long tumor retention, multi-responsive boronate crosslinked micelles (BCM) for ovarian cancer therapy. We systemically investigated the stability of BCM in serum and plasma, and their responsiveness to acidic pH and cis-diols (such as mannitol, a safe FDA approved drug for diuresis) through particle size measurement and förster resonance energy transfer (FRET) approach. Paclitaxel (PTX) loaded BCM (BCM-PTX) exhibited higher stability than non-crosslinked micelles (NCM) in the presence of plasma or serum. BCMs possessed a longer in vivo blood circulation time when compared to NCM. Furthermore, BCM could be disassembled in an acidic pH environment or by administrating mannitol, facilitating drug release in an acidic tumor environment and triggered by exogenous stimuli after drug enrichment in tumor mass. Near infra-red fluorescence (NIRF) imaging on SKOV-3 ovarian cancer mouse model demonstrated that the NIR dye DiD encapsulated BCM could preferentially accumulate in tumor site and their tumor retention was very long with still 66% remained on 12th day post injection. DiD-NCM had similar high-level uptake in tumor with DiD-BCM within the first 3 days, its accumulation, however, decreased obviously on 4th day and only 15% dye was left 12 days later. In both formulations, the dye uptake in normal organs was mostly washed away within the first 24–48 h. In in vivo tumor treatment study, PTX loaded BCM showed superior therapeutic efficacy than that of NCM and Taxol. The mice could tolerate 20 mg/kg PTX formulated in nano-formulations, which doubled the maximum tolerated dose (MTD) of Taxol. The administration of mannitol 24 h after BCM-PTX injection further improved the tumor therapeutic effect and elongated the survival time of the mice. The novel boronate-catechol crosslinked nanocarrier platform demonstrated its superior capability in targeted drug delivery, which is not only useful for ovarian cancer treatment but will also be beneficial for the therapy of many other solid tumors.

Original languageEnglish (US)
Pages (from-to)169-179
Number of pages11
JournalJournal of Controlled Release
Volume264
DOIs
StatePublished - Oct 28 2017

Fingerprint

Micelles
Ovarian Neoplasms
Paclitaxel
Neoplasms
Therapeutics
Mannitol
Pharmaceutical Preparations
Coloring Agents
Blood Circulation Time
Drug Therapy
Injections
Maximum Tolerated Dose
Blood Circulation
Optical Imaging
Diuresis
Energy Transfer
Therapeutic Uses
Standard of Care
Serum
Particle Size

Keywords

  • Boronate crosslinked micelles
  • FRET
  • Long-term tumor retention
  • Multi-responsive
  • Ovarian cancer

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Extremely long tumor retention, multi-responsive boronate crosslinked micelles with superior therapeutic efficacy for ovarian cancer. / Xiao, Wenwu; Suby, Nell; Xiao, Kai; Lin, Tzu-Yin; Al Awwad, Nasir; Lam, Kit; Li, Yuanpei.

In: Journal of Controlled Release, Vol. 264, 28.10.2017, p. 169-179.

Research output: Contribution to journalArticle

@article{d44115da68914ad6a44a60511193a94e,
title = "Extremely long tumor retention, multi-responsive boronate crosslinked micelles with superior therapeutic efficacy for ovarian cancer",
abstract = "Mortality rates for ovarian cancer have declined only slightly in the past forty years since the “War on Cancer” was declared. The current standard care of ovarian cancer is still cytoredutive surgery followed by several cycles of chemotherapy. The severe adverse effect from chemotherapy drug is a leading cause for the patients to fail in long term therapy post-surgery. New nanocarriers able to minimize the premature drug release in blood circulation while releasing drug on-demand at tumor site have profound impact on the improvement of the efficacy and toxicity profile of the chemotherapeutic drugs. Here we reported a unique type of extremely long tumor retention, multi-responsive boronate crosslinked micelles (BCM) for ovarian cancer therapy. We systemically investigated the stability of BCM in serum and plasma, and their responsiveness to acidic pH and cis-diols (such as mannitol, a safe FDA approved drug for diuresis) through particle size measurement and f{\"o}rster resonance energy transfer (FRET) approach. Paclitaxel (PTX) loaded BCM (BCM-PTX) exhibited higher stability than non-crosslinked micelles (NCM) in the presence of plasma or serum. BCMs possessed a longer in vivo blood circulation time when compared to NCM. Furthermore, BCM could be disassembled in an acidic pH environment or by administrating mannitol, facilitating drug release in an acidic tumor environment and triggered by exogenous stimuli after drug enrichment in tumor mass. Near infra-red fluorescence (NIRF) imaging on SKOV-3 ovarian cancer mouse model demonstrated that the NIR dye DiD encapsulated BCM could preferentially accumulate in tumor site and their tumor retention was very long with still 66{\%} remained on 12th day post injection. DiD-NCM had similar high-level uptake in tumor with DiD-BCM within the first 3 days, its accumulation, however, decreased obviously on 4th day and only 15{\%} dye was left 12 days later. In both formulations, the dye uptake in normal organs was mostly washed away within the first 24–48 h. In in vivo tumor treatment study, PTX loaded BCM showed superior therapeutic efficacy than that of NCM and Taxol. The mice could tolerate 20 mg/kg PTX formulated in nano-formulations, which doubled the maximum tolerated dose (MTD) of Taxol. The administration of mannitol 24 h after BCM-PTX injection further improved the tumor therapeutic effect and elongated the survival time of the mice. The novel boronate-catechol crosslinked nanocarrier platform demonstrated its superior capability in targeted drug delivery, which is not only useful for ovarian cancer treatment but will also be beneficial for the therapy of many other solid tumors.",
keywords = "Boronate crosslinked micelles, FRET, Long-term tumor retention, Multi-responsive, Ovarian cancer",
author = "Wenwu Xiao and Nell Suby and Kai Xiao and Tzu-Yin Lin and {Al Awwad}, Nasir and Kit Lam and Yuanpei Li",
year = "2017",
month = "10",
day = "28",
doi = "10.1016/j.jconrel.2017.08.028",
language = "English (US)",
volume = "264",
pages = "169--179",
journal = "Journal of Controlled Release",
issn = "0168-3659",
publisher = "Elsevier",

}

TY - JOUR

T1 - Extremely long tumor retention, multi-responsive boronate crosslinked micelles with superior therapeutic efficacy for ovarian cancer

AU - Xiao, Wenwu

AU - Suby, Nell

AU - Xiao, Kai

AU - Lin, Tzu-Yin

AU - Al Awwad, Nasir

AU - Lam, Kit

AU - Li, Yuanpei

PY - 2017/10/28

Y1 - 2017/10/28

N2 - Mortality rates for ovarian cancer have declined only slightly in the past forty years since the “War on Cancer” was declared. The current standard care of ovarian cancer is still cytoredutive surgery followed by several cycles of chemotherapy. The severe adverse effect from chemotherapy drug is a leading cause for the patients to fail in long term therapy post-surgery. New nanocarriers able to minimize the premature drug release in blood circulation while releasing drug on-demand at tumor site have profound impact on the improvement of the efficacy and toxicity profile of the chemotherapeutic drugs. Here we reported a unique type of extremely long tumor retention, multi-responsive boronate crosslinked micelles (BCM) for ovarian cancer therapy. We systemically investigated the stability of BCM in serum and plasma, and their responsiveness to acidic pH and cis-diols (such as mannitol, a safe FDA approved drug for diuresis) through particle size measurement and förster resonance energy transfer (FRET) approach. Paclitaxel (PTX) loaded BCM (BCM-PTX) exhibited higher stability than non-crosslinked micelles (NCM) in the presence of plasma or serum. BCMs possessed a longer in vivo blood circulation time when compared to NCM. Furthermore, BCM could be disassembled in an acidic pH environment or by administrating mannitol, facilitating drug release in an acidic tumor environment and triggered by exogenous stimuli after drug enrichment in tumor mass. Near infra-red fluorescence (NIRF) imaging on SKOV-3 ovarian cancer mouse model demonstrated that the NIR dye DiD encapsulated BCM could preferentially accumulate in tumor site and their tumor retention was very long with still 66% remained on 12th day post injection. DiD-NCM had similar high-level uptake in tumor with DiD-BCM within the first 3 days, its accumulation, however, decreased obviously on 4th day and only 15% dye was left 12 days later. In both formulations, the dye uptake in normal organs was mostly washed away within the first 24–48 h. In in vivo tumor treatment study, PTX loaded BCM showed superior therapeutic efficacy than that of NCM and Taxol. The mice could tolerate 20 mg/kg PTX formulated in nano-formulations, which doubled the maximum tolerated dose (MTD) of Taxol. The administration of mannitol 24 h after BCM-PTX injection further improved the tumor therapeutic effect and elongated the survival time of the mice. The novel boronate-catechol crosslinked nanocarrier platform demonstrated its superior capability in targeted drug delivery, which is not only useful for ovarian cancer treatment but will also be beneficial for the therapy of many other solid tumors.

AB - Mortality rates for ovarian cancer have declined only slightly in the past forty years since the “War on Cancer” was declared. The current standard care of ovarian cancer is still cytoredutive surgery followed by several cycles of chemotherapy. The severe adverse effect from chemotherapy drug is a leading cause for the patients to fail in long term therapy post-surgery. New nanocarriers able to minimize the premature drug release in blood circulation while releasing drug on-demand at tumor site have profound impact on the improvement of the efficacy and toxicity profile of the chemotherapeutic drugs. Here we reported a unique type of extremely long tumor retention, multi-responsive boronate crosslinked micelles (BCM) for ovarian cancer therapy. We systemically investigated the stability of BCM in serum and plasma, and their responsiveness to acidic pH and cis-diols (such as mannitol, a safe FDA approved drug for diuresis) through particle size measurement and förster resonance energy transfer (FRET) approach. Paclitaxel (PTX) loaded BCM (BCM-PTX) exhibited higher stability than non-crosslinked micelles (NCM) in the presence of plasma or serum. BCMs possessed a longer in vivo blood circulation time when compared to NCM. Furthermore, BCM could be disassembled in an acidic pH environment or by administrating mannitol, facilitating drug release in an acidic tumor environment and triggered by exogenous stimuli after drug enrichment in tumor mass. Near infra-red fluorescence (NIRF) imaging on SKOV-3 ovarian cancer mouse model demonstrated that the NIR dye DiD encapsulated BCM could preferentially accumulate in tumor site and their tumor retention was very long with still 66% remained on 12th day post injection. DiD-NCM had similar high-level uptake in tumor with DiD-BCM within the first 3 days, its accumulation, however, decreased obviously on 4th day and only 15% dye was left 12 days later. In both formulations, the dye uptake in normal organs was mostly washed away within the first 24–48 h. In in vivo tumor treatment study, PTX loaded BCM showed superior therapeutic efficacy than that of NCM and Taxol. The mice could tolerate 20 mg/kg PTX formulated in nano-formulations, which doubled the maximum tolerated dose (MTD) of Taxol. The administration of mannitol 24 h after BCM-PTX injection further improved the tumor therapeutic effect and elongated the survival time of the mice. The novel boronate-catechol crosslinked nanocarrier platform demonstrated its superior capability in targeted drug delivery, which is not only useful for ovarian cancer treatment but will also be beneficial for the therapy of many other solid tumors.

KW - Boronate crosslinked micelles

KW - FRET

KW - Long-term tumor retention

KW - Multi-responsive

KW - Ovarian cancer

UR - http://www.scopus.com/inward/record.url?scp=85028509313&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85028509313&partnerID=8YFLogxK

U2 - 10.1016/j.jconrel.2017.08.028

DO - 10.1016/j.jconrel.2017.08.028

M3 - Article

C2 - 28847739

AN - SCOPUS:85028509313

VL - 264

SP - 169

EP - 179

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

ER -