In vivo biodistribution of siRNA and cisplatin administered using CD44-targeted hyaluronic acid nanoparticles

Abstract

Multidrug resistance (MDR) is a significant problem in the clinical management of several cancers. Overcoming MDR generally involves multi-modal therapeutic approaches that integrates enhancement of delivery efficiency using targeted nano-platforms as well as strategies that can sensitize cancer cells to drug treatments. We recently demonstrated that tandem delivery of siRNAs that downregulate anti-apoptotic genes overexpressed in cisplatin resistant tumors followed by therapeutic challenge using cisplatin loaded in CD44 targeted hyaluronic acid (HA) nanoparticles (NPs) induced synergistic antitumor response in CD44 expressing tumors that are resistant to cisplatin. In the current study, a near infrared (NIR) dye-loaded HA NPs was employed to image the whole body localization of NPs after intravenous (i.v.) injection into live mice bearing human lung tumors that were sensitive and resistant to cisplatin. In addition, we quantified the siRNA duplexes and cisplatin dose distribution in various tissues and organs using an ultra-sensitive quantitative PCR method and inductively coupled plasma-mass spectrometry (ICP-MS), respectively, after i.v. injection of the payload loaded HA NPs in tumor bearing mice. Our findings demonstrate that the distribution pattern of the siRNA and cisplatin using specifically engineered CD44 targeting HA NPs correlated well with the tumor targeting capability as well as the activity and efficacy obtained with combination treatments.

Near-infrared fluorescent probes in cancer imaging and therapy: an emerging field

“…Effective delivery of chemical drugs to tumor sites is particularly appealing for the enhancement of the tumor-killing effect and the reduction of systemic toxicities. 187,188 It was revealed that drug-loaded NP systems accumulate in tumors through the EPR effect, which increases drug bioavailability and prolongs the exposure to therapeutic agents. 189 Rapid uptake and retention of polymer conjugates in the lymphatic system have also been observed with low toxicity.…”

Biodistribution and Pharmacokinetics of Mad2 siRNA-loaded EGFR-Targeted Chitosan Nanoparticles in Cisplatin Sensitive and Resistant Lung Cancer Models

“…The procedure was performed according to the previously optimized protocol published by our group [47]. Briefly, 6 μl of diluted tissue sample was mixed with 18 μl of 100 nM reverse primer, and put through a cycle of denaturation by incubating at 95°C for 5 min and another cycle of annealing for 2 min at each temperature of 80, 70, 60 and 45°C.…”

Translational Nano-Medicines: Targeted Therapeutic Delivery for Cancer and Inflammatory Diseases

“…Overexpression of bcl-2 is known to delay the onset of apoptosis induced by several chemotherapeutic drugs. Evidence reported indicates that downregulation of antiapoptotic genes such as survivin and bcl-2 can sensitize cancer cells to anticancer drugs (45,46). We have previously observed the effect of combining siRNA and cisplatin in CD44-targeting hyaluronic acid (HA)-based self-assembling nanosystems reversed drug resistance and delayed the tumor growth significantly (growth inhibition increased from 30 to 60%) in cisplatin-resistant tumors without indication of non-specific toxicity (Fig.…”