Temperature/pH/Enzyme Triple-Responsive Cationic Protein/PAA-b-PNIPAAm Nanogels for Controlled Anticancer Drug and Photosensitizer Delivery against Multidrug Resistant Breast Cancer Cells

Trong Ming Don, Kun Ying Lu, Li Jie Lin, Chun Hua Hsu, Jui Yu Wu, Fwu Long Mi

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The tumor microenvironments are often acidic and overexpress specific enzymes. In this work, we synthesized a poly(AA-b-NIPAAm) copolymer (PAA-b-PNIPAAm) using a reversible addition-fragmentation chain transfer (RAFT) polymerization method. PAA-b-PNIPAAm and a cationic protein (protamine) were self-assembled into nanogels, which effectively reduced the cytotoxicity of protamine. The protamine/PAA-b-PNIPAAm nanogels were responsive to the stimuli including temperature, pH, and enzyme due to disaggregation of PAA-b-PNIPAAm, change in random coil/α-helix conformation of protamine, and enzymatic hydrolysis of the protein. Changing the pH from 7.4 to a lowered pHe (6.5-5.0) resulted in an increase in mean particle size and smartly converted surface charge from negative to positive. The cationic nanogels easily passed through the cell membrane and enhanced intracellular localization and accumulation of doxorubicin-loaded nanogels in multidrug resistant MCF-7/ADR breast cancer cells. Cold shock treatment triggered rapid intracellular release of doxorubicin against P-glycoprotein (Pgp)-mediated drug efflux, showing significantly improved anticancer efficacy as compared with free DOX. Furthermore, the nanogels were able to carry a rose bengal photosensitizer and caused significant damage to the multidrug resistant cancer cells under irradiation. The cationic nanogels with stimuli-responsive properties show promise as drug carrier for chemotherapy and photodynamic therapy against cancers.

Original languageEnglish
Pages (from-to)4648-4660
Number of pages13
JournalMolecular Pharmaceutics
Volume14
Issue number12
DOIs
Publication statusPublished - Dec 4 2017

Fingerprint

Photosensitizing Agents
Protamines
Breast Neoplasms
Temperature
Enzymes
Pharmaceutical Preparations
Proteins
Doxorubicin
Rose Bengal
Drug Carriers
Tumor Microenvironment
Photochemotherapy
P-Glycoprotein
Particle Size
Polymerization
poly-N-isopropylacrylamide
NanoGel
Shock
Neoplasms
Hydrolysis

Keywords

  • enzymatic digestion
  • N-isopropylacrylamide
  • nanogels
  • pH-responsive
  • protamine
  • thermoresponsive

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

Temperature/pH/Enzyme Triple-Responsive Cationic Protein/PAA-b-PNIPAAm Nanogels for Controlled Anticancer Drug and Photosensitizer Delivery against Multidrug Resistant Breast Cancer Cells. / Don, Trong Ming; Lu, Kun Ying; Lin, Li Jie; Hsu, Chun Hua; Wu, Jui Yu; Mi, Fwu Long.

In: Molecular Pharmaceutics, Vol. 14, No. 12, 04.12.2017, p. 4648-4660.

Research output: Contribution to journalArticle

@article{e0f1a168824449ddbb44aa5d9af8e4db,
title = "Temperature/pH/Enzyme Triple-Responsive Cationic Protein/PAA-b-PNIPAAm Nanogels for Controlled Anticancer Drug and Photosensitizer Delivery against Multidrug Resistant Breast Cancer Cells",
abstract = "The tumor microenvironments are often acidic and overexpress specific enzymes. In this work, we synthesized a poly(AA-b-NIPAAm) copolymer (PAA-b-PNIPAAm) using a reversible addition-fragmentation chain transfer (RAFT) polymerization method. PAA-b-PNIPAAm and a cationic protein (protamine) were self-assembled into nanogels, which effectively reduced the cytotoxicity of protamine. The protamine/PAA-b-PNIPAAm nanogels were responsive to the stimuli including temperature, pH, and enzyme due to disaggregation of PAA-b-PNIPAAm, change in random coil/α-helix conformation of protamine, and enzymatic hydrolysis of the protein. Changing the pH from 7.4 to a lowered pHe (6.5-5.0) resulted in an increase in mean particle size and smartly converted surface charge from negative to positive. The cationic nanogels easily passed through the cell membrane and enhanced intracellular localization and accumulation of doxorubicin-loaded nanogels in multidrug resistant MCF-7/ADR breast cancer cells. Cold shock treatment triggered rapid intracellular release of doxorubicin against P-glycoprotein (Pgp)-mediated drug efflux, showing significantly improved anticancer efficacy as compared with free DOX. Furthermore, the nanogels were able to carry a rose bengal photosensitizer and caused significant damage to the multidrug resistant cancer cells under irradiation. The cationic nanogels with stimuli-responsive properties show promise as drug carrier for chemotherapy and photodynamic therapy against cancers.",
keywords = "enzymatic digestion, N-isopropylacrylamide, nanogels, pH-responsive, protamine, thermoresponsive",
author = "Don, {Trong Ming} and Lu, {Kun Ying} and Lin, {Li Jie} and Hsu, {Chun Hua} and Wu, {Jui Yu} and Mi, {Fwu Long}",
year = "2017",
month = "12",
day = "4",
doi = "10.1021/acs.molpharmaceut.7b00737",
language = "English",
volume = "14",
pages = "4648--4660",
journal = "Molecular Pharmaceutics",
issn = "1543-8384",
publisher = "American Chemical Society",
number = "12",

}

TY - JOUR

T1 - Temperature/pH/Enzyme Triple-Responsive Cationic Protein/PAA-b-PNIPAAm Nanogels for Controlled Anticancer Drug and Photosensitizer Delivery against Multidrug Resistant Breast Cancer Cells

AU - Don, Trong Ming

AU - Lu, Kun Ying

AU - Lin, Li Jie

AU - Hsu, Chun Hua

AU - Wu, Jui Yu

AU - Mi, Fwu Long

PY - 2017/12/4

Y1 - 2017/12/4

N2 - The tumor microenvironments are often acidic and overexpress specific enzymes. In this work, we synthesized a poly(AA-b-NIPAAm) copolymer (PAA-b-PNIPAAm) using a reversible addition-fragmentation chain transfer (RAFT) polymerization method. PAA-b-PNIPAAm and a cationic protein (protamine) were self-assembled into nanogels, which effectively reduced the cytotoxicity of protamine. The protamine/PAA-b-PNIPAAm nanogels were responsive to the stimuli including temperature, pH, and enzyme due to disaggregation of PAA-b-PNIPAAm, change in random coil/α-helix conformation of protamine, and enzymatic hydrolysis of the protein. Changing the pH from 7.4 to a lowered pHe (6.5-5.0) resulted in an increase in mean particle size and smartly converted surface charge from negative to positive. The cationic nanogels easily passed through the cell membrane and enhanced intracellular localization and accumulation of doxorubicin-loaded nanogels in multidrug resistant MCF-7/ADR breast cancer cells. Cold shock treatment triggered rapid intracellular release of doxorubicin against P-glycoprotein (Pgp)-mediated drug efflux, showing significantly improved anticancer efficacy as compared with free DOX. Furthermore, the nanogels were able to carry a rose bengal photosensitizer and caused significant damage to the multidrug resistant cancer cells under irradiation. The cationic nanogels with stimuli-responsive properties show promise as drug carrier for chemotherapy and photodynamic therapy against cancers.

AB - The tumor microenvironments are often acidic and overexpress specific enzymes. In this work, we synthesized a poly(AA-b-NIPAAm) copolymer (PAA-b-PNIPAAm) using a reversible addition-fragmentation chain transfer (RAFT) polymerization method. PAA-b-PNIPAAm and a cationic protein (protamine) were self-assembled into nanogels, which effectively reduced the cytotoxicity of protamine. The protamine/PAA-b-PNIPAAm nanogels were responsive to the stimuli including temperature, pH, and enzyme due to disaggregation of PAA-b-PNIPAAm, change in random coil/α-helix conformation of protamine, and enzymatic hydrolysis of the protein. Changing the pH from 7.4 to a lowered pHe (6.5-5.0) resulted in an increase in mean particle size and smartly converted surface charge from negative to positive. The cationic nanogels easily passed through the cell membrane and enhanced intracellular localization and accumulation of doxorubicin-loaded nanogels in multidrug resistant MCF-7/ADR breast cancer cells. Cold shock treatment triggered rapid intracellular release of doxorubicin against P-glycoprotein (Pgp)-mediated drug efflux, showing significantly improved anticancer efficacy as compared with free DOX. Furthermore, the nanogels were able to carry a rose bengal photosensitizer and caused significant damage to the multidrug resistant cancer cells under irradiation. The cationic nanogels with stimuli-responsive properties show promise as drug carrier for chemotherapy and photodynamic therapy against cancers.

KW - enzymatic digestion

KW - N-isopropylacrylamide

KW - nanogels

KW - pH-responsive

KW - protamine

KW - thermoresponsive

UR - http://www.scopus.com/inward/record.url?scp=85037640260&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85037640260&partnerID=8YFLogxK

U2 - 10.1021/acs.molpharmaceut.7b00737

DO - 10.1021/acs.molpharmaceut.7b00737

M3 - Article

VL - 14

SP - 4648

EP - 4660

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 12

ER -