Targeted therapeutic nanotubes influence the viscoelasticity of cancer cells to overcome drug resistance.
Resistance to chemotherapy is the primary cause of treatment failure in over 90% of cancer patients in the clinic. Research in nanotechnology-based therapeutic alternatives has helped provide innovative and promising strategies to overcome multidrug resistance (MDR). By targeting CD44-overexpressing MDR cancer cells, we have developed in a single-step a self-assembled, self-targetable, therapeutic semiconducting single-walled carbon nanotube (sSWCNT) drug delivery system that can deliver chemotherapeutic agents to both drug-sensitive OVCAR8 and resistant OVCAR8/ADR cancer cells. The novel nanoformula with a cholanic acid-derivatized hyaluronic acid (CAHA) biopolymer wrapped around a sSWCNT and loaded with doxorubicin (DOX), CAHA-sSWCNT-DOX, is much more effective in killing drug-resistant cancer cells compared to the free DOX and phospholipid PEG (PL-PEG)-modified sSWCNT formula, PEG-sSWCNT-DOX. The CAHA-sSWCNT-DOX affects the viscoelastic property more than free DOX and PL-PEG-sSWCNT-DOX, which in turn allows more drug molecules to be internalized. Intravenous injection of CAHA-sSWCNT-DOX (12 mg/kg DOX equivalent) followed by 808 nm laser irradiation (1 W/cm(2), 90 s) led to complete tumor eradication in a subcutaneous OVCAR8/ADR drug-resistant xenograft model, while free DOX alone failed to delay tumor growth. Our newly developed CAHA-sSWCNT-DOX nanoformula, which delivers therapeutics and acts as a sensitizer to influence drug uptake and induce apoptosis with minimal resistance factor, provides a novel effective means of counteracting the phenomenon of multidrug resistance.
Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health , Bethesda, Maryland 20892, United States.
Ashwinkumar A
AA
Bhirde
Bhaskara V
BV
Chikkaveeraiah
Avinash
A
Srivatsan
Gang
G
Niu
Albert J
AJ
Jin
Ankur
A
Kapoor
Zhe
Z
Wang
Sachin
S
Patel
Vyomesh
V
Patel
Alexander M
AM
Gorbach
Richard D
RD
Leapman
J Silvio
JS
Gutkind
Angela R
AR
Hight Walker
Xiaoyuan
X
Chen
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage; D004337:Drug Carriers; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004548:Elasticity; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D036103:Nanotechnology / Q000379:methods*; D043942:Nanotubes / Q000737:chemistry*; D037742:Nanotubes, Carbon / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010743:Phospholipids / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D058525:Quartz Crystal Microbalance Techniques; D012666:Semiconductors; D013696:Temperature; D014783:Viscosity
D004337:Drug Carriers; D037742:Nanotubes, Carbon; D010743:Phospholipids; D011108:Polymers; D011092:Polyethylene Glycols; D004317:Doxorubicin