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A Sequentially Responsive Nanosystem Breaches Cascaded Bio-barriers and Suppresses P-Glycoprotein Function for Reversing Cancer Drug Resistance.
- Source :
-
ACS applied materials & interfaces [ACS Appl Mater Interfaces] 2020 Dec 09; Vol. 12 (49), pp. 54343-54355. Date of Electronic Publication: 2020 Nov 24. - Publication Year :
- 2020
-
Abstract
- Cancer chemotherapy is challenged by multidrug resistance (MDR) mainly attributed to overexpressed transmembrane efflux pump P-glycoprotein (P-gp) in cancer cells. Improving drug delivery efficacy while co-delivering P-gp inhibitors to suppress drug efflux is an often-used nanostrategy for combating MDR, which is however challenged by cascaded bio-barriers en route to cancer cells and P-gp inhibitors' adverse effects. To effectively breach the cascaded bio-barriers while avoiding P-gp inhibitors' adverse effects, a stealthy, sequentially responsive doxorubicin (DOX) delivery nanosystem (RCMSNs) is fabricated, composed of an extracellular-tumor-acidity-responsive polymer shell (PEG- b -PLLDA), pH/redox dual-responsive mesoporous silica nanoparticle-based carriers (MSNs-SS-Py), and cationic β-cyclodextrin-PEI (CD-PEI) gatekeepers. The PEG- b -PLLDA corona makes RCMSNs stealthy with prolonged blood circulation time. Once tumors are reached, extracellular acidity degrades PEG- b -PLLDA, reversing nanosystem's surface charges to be positive, which drastically improves RCMSNs' tumor accumulation, penetration, and cellular internalization. Within cancer cells, CD-PEI gatekeepers detach to allow DOX unloading in response to intracellular acidity and glutathione and functionally act as a P-gp inhibitor, dampening P-gp's efflux activity by impairing ATP production. Thus, the resultant high-efficacy drug delivery along with reduced P-gp function cooperatively reverses MDR in vitro . Importantly, in preclinical tumor models, DOX@RCMSNs potently suppress MDR tumor growth without eliciting systemic toxicity, demonstrating their potential of clinical translation.
- Subjects :
- Adenosine Triphosphate metabolism
Animals
Antibiotics, Antineoplastic chemistry
Antibiotics, Antineoplastic metabolism
Antibiotics, Antineoplastic pharmacology
Doxorubicin metabolism
Doxorubicin pharmacology
Drug Carriers metabolism
Drug Liberation
Drug Resistance, Neoplasm drug effects
Female
Humans
Hydrogen-Ion Concentration
MCF-7 Cells
Mice
Mice, Inbred BALB C
Nanoparticles metabolism
Polymers chemistry
Porosity
Silicon Dioxide chemistry
Tissue Distribution
beta-Cyclodextrins chemistry
ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
Doxorubicin chemistry
Drug Carriers chemistry
Nanoparticles chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1944-8252
- Volume :
- 12
- Issue :
- 49
- Database :
- MEDLINE
- Journal :
- ACS applied materials & interfaces
- Publication Type :
- Academic Journal
- Accession number :
- 32959645
- Full Text :
- https://doi.org/10.1021/acsami.0c13852