32 research outputs found
Recommended from our members
Nanodrug-Enhanced Radiofrequency Tumor Ablation: Effect of Micellar or Liposomal Carrier on Drug Delivery and Treatment Efficacy
Purpose To determine the effect of different drug-loaded nanocarriers (micelles and liposomes) on delivery and treatment efficacy for radiofrequency ablation (RFA) combined with nanodrugs. Materials/Methods Fischer 344 rats were used (n = 196). First, single subcutaneous R3230 tumors or normal liver underwent RFA followed by immediate administration of IV fluorescent beads (20, 100, and 500 nm), with fluorescent intensity measured at 4–24 hr. Next, to study carrier type on drug efficiency, RFA was combined with micellar (20 nm) or liposomal (100 nm) preparations of doxorubicin (Dox; targeting HIF-1α) or quercetin (Qu; targeting HSP70). Animals received RFA alone, RFA with Lipo-Dox or Mic-Dox (1 mg IV, 15 min post-RFA), and RFA with Lipo-Qu or Mic-Qu given 24 hr pre- or 15 min post-RFA (0.3 mg IV). Tumor coagulation and HIF-1α orHSP70 expression were assessed 24 hr post-RFA. Third, the effect of RFA combined with IV Lipo-Dox, Mic-Dox, Lipo-Qu, or Mic-Qu (15 min post-RFA) compared to RFA alone on tumor growth and animal endpoint survival was evaluated. Finally, drug uptake was compared between RFA/Lipo-Dox and RFA/Mic-Dox at 4–72 hr. Results: Smaller 20 nm beads had greater deposition and deeper tissue penetration in both tumor (100 nm/500 nm) and liver (100 nm) (p<0.05). Mic-Dox and Mic-Qu suppressed periablational HIF-1α or HSP70 rim thickness more than liposomal preparations (p<0.05). RFA/Mic-Dox had greater early (4 hr) intratumoral doxorubicin, but RFA/Lipo-Dox had progressively higher intratumoral doxorubicin at 24–72 hr post-RFA (p<0.04). No difference in tumor growth and survival was seen between RFA/Lipo-Qu and RFA/Mic-Qu. Yet, RFA/Lipo-Dox led to greater animal endpoint survival compared to RFA/Mic-Dox (p<0.03). Conclusion: With RF ablation, smaller particle micelles have superior penetration and more effective local molecular modulation. However, larger long-circulating liposomal carriers can result in greater intratumoral drug accumulation over time and reduced tumor growth. Accordingly, different carriers provide specific advantages, which should be considered when formulating optimal combination therapies
P-glycoprotein silencing with siRNA delivered by DOPEmodified PEI overcomes doxorubicin resistance in breast cancer cells
AIMS:
Multidrug resistance (MDR) mediated by overexpression of drug efflux transporters such as P-glycoprotein (P-gp), is a major problem, limiting successful chemotherapy of breast cancer. The use of siRNA to inhibit P-gp expression in MDR tumors is an attractive strategy to improve the effectiveness of anticancer drugs.
METHOD:
We have synthesized a novel conjugate between a phospholipid (dioleoylphosphatidylethanolamine) and polyethylenimine (PEI) for siRNA delivery, for the purpose of silencing P-gp to overcome doxorubicin resistance in MCF-7 human breast cancer cells.
RESULTS:
The dioleoylphosphatidylethanolamine-PEI conjugate enhanced the transfection efficacy of low-molecular-weight PEI, which was otherwise totally ineffective. In addition, the polyethylene glycol/lipid coating of the new complexes gave rise to small micelle-like nanoparticles with improved biocompatibility properties. Both coated and noncoated formulations delivered P-gp-specific siRNA to MDR cells.
DISCUSSION:
The combination of doxorubicin and P-gp silencing formulations led to a twofold increase of doxorubicin uptake and a significant improvement of the therapeutic effect of doxorubicin in resistant cells
EGFR Targeted Theranostic Nanoemulsion for Image-Guided Ovarian Cancer Therapy
Platinum-based therapies are the first line treatments for most types of cancer including ovarian cancer. However, their use is associated with dose-limiting toxicities and resistance. We report initial translational studies of a theranostic nanoemulsion loaded with a cisplatin derivative, myrisplatin and pro-apoptotic agent, C6-ceramide
P-glycoprotein silencing with siRNA delivered by DOPEmodified PEI overcomes doxorubicin resistance in breast cancer cells
AIMS:
Multidrug resistance (MDR) mediated by overexpression of drug efflux transporters such as P-glycoprotein (P-gp), is a major problem, limiting successful chemotherapy of breast cancer. The use of siRNA to inhibit P-gp expression in MDR tumors is an attractive strategy to improve the effectiveness of anticancer drugs.
METHOD:
We have synthesized a novel conjugate between a phospholipid (dioleoylphosphatidylethanolamine) and polyethylenimine (PEI) for siRNA delivery, for the purpose of silencing P-gp to overcome doxorubicin resistance in MCF-7 human breast cancer cells.
RESULTS:
The dioleoylphosphatidylethanolamine-PEI conjugate enhanced the transfection efficacy of low-molecular-weight PEI, which was otherwise totally ineffective. In addition, the polyethylene glycol/lipid coating of the new complexes gave rise to small micelle-like nanoparticles with improved biocompatibility properties. Both coated and noncoated formulations delivered P-gp-specific siRNA to MDR cells.
DISCUSSION:
The combination of doxorubicin and P-gp silencing formulations led to a twofold increase of doxorubicin uptake and a significant improvement of the therapeutic effect of doxorubicin in resistant cells
Targeted Transferrin-Modified Polymeric Micelles: Enhanced Efficacy in Vitro and in Vivo in Ovarian Carcinoma
In this study, transferrin (Tf)-modified
polyÂ(ethylene glycol)-phosphatidylethanolamine
(mPEG-PE) micelles loaded with the poorly water-soluble drug, R547
(a potent and selective ATP-competitive cyclin-dependent kinase (CDK)
inhibitor), were prepared and evaluated for their targeting efficiency
and cytotoxicity in vitro and in vivo to A2780 ovarian carcinoma cells,
which overexpress transferrin receptors (TfR). At 10 mM lipid concentration,
both Tf-modified and plain micelles solubilized 800 ÎĽg of R547.
Tf-modified micelles showed enhanced interaction with A2780 ovarian
carcinoma cells in vitro. The involvement of TfR in endocytosis of
Tf-modified micelles was confirmed by colocalization studies of micelle-treated
cells with the endosomal marker Tf-Alexa488. We confirmed endocytosis
of micelles in an intact form with micelles loaded with a fluorescent
dye and additionally labeled with fluorescent lipid. The in vitro
cytotoxicity and in vivo tumor growth inhibition studies in A2780-tumor
bearing mice confirmed the enhanced efficacy of Tf-modified R547-loaded
micelles compared to free drug solution and to nonmodified micelles.
The results of this study demonstrate the potential application of
Tf-conjugated polymeric micelles in the treatment of tumors overexpressing
TfR