Co-delivery of CPP decorated doxorubicin and CPP decorated siRNA by NGR-modified nanobubbles for improving anticancer
Rui Ma1,2, Jingxue Nai3,4, Jinbang Zhang3,5
1Chinese PLA Medical School, Pharmaceutical Sciences Research Division, Beijing, China.
Abstract:
A combination of doxorubicin (DOX) and small interfering RNA (siRNA) is proven effective for the reverse of multidrug resistance. However, rapid degradation and poor cellular internalization of siRNA hinder their synergistic action. To improve the combination effect, asparagine-glycine-arginine peptide (NGR) -modified nanobubbles (NBs) containing cell-penetrating peptide (CPP) decorated DOX and CPP decorated c-myc siRNA were constructed. Diameters of these NBs were about 245 nm and zeta potentials were about -3 mV. Encapsulation efficiencies (EE) of DOX exceeded 80%. Release of DOX could be triggered by ultrasound (US) since above 80% DOX was released from NBs after sonication while less than 5% DOX was discharged without treatment of US. These NBs were considered stable during 24 h since the decrease of particle size was no more than 10 nm, variances of EE were less than 5%, and changes of transmission (ΔT) were less than 3%. More drugs in formulation decorated with CPP and NGR were accumulated in the tumor when combined with sonication. The evident synergistic action of DOX, siRNA, NBs, and US was verified in mice with strong antitumor efficacy. Taken together, NGR-modified NBs containing CPP-DOX and CPP-siRNA are able to realize time- and spatial-controlled drug delivery and show potential application prospects.
Insights
This study developed novel nanobubbles (NBs) combining doxorubicin (DOX) and small interfering RNA (siRNA) for enhanced cancer therapy. These NGR-modified NBs show significant potential for targeted drug delivery and overcoming multidrug resistance.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Multidrug resistance (MDR) in cancer limits treatment efficacy.
- Doxorubicin (DOX) and small interfering RNA (siRNA) show synergistic potential against MDR.
- Poor siRNA stability and cellular uptake impede combined therapy effectiveness.
Purpose of the Study:
- To develop novel nanobubbles (NBs) for enhanced delivery of DOX and siRNA.
- To improve the synergistic anticancer effect of DOX and siRNA.
- To achieve targeted and controlled release of therapeutic agents.
Main Methods:
- Construction of asparagine-glycine-arginine peptide (NGR)-modified nanobubbles (NBs).
- Encapsulation of cell-penetrating peptide (CPP)-decorated DOX and CPP-decorated c-myc siRNA within NBs.
- Characterization of NB size, zeta potential, encapsulation efficiency, stability, and drug release kinetics.
- In vivo evaluation of tumor accumulation and antitumor efficacy in mice.
Main Results:
- NBs demonstrated stable characteristics (245 nm size, -3 mV zeta potential) with high DOX encapsulation (>80%).
- Ultrasound (US) triggered significant DOX release (>80%) from NBs.
- NGR-modified NBs enhanced tumor drug accumulation when combined with US.
- Synergistic action of DOX, siRNA, NBs, and US exhibited strong antitumor efficacy in vivo.
Conclusions:
- NGR-modified NBs facilitate time- and spatial-controlled delivery of CPP-DOX and CPP-siRNA.
- This nanobubble formulation shows promise for overcoming MDR and improving cancer treatment.
- The developed system offers potential for advanced therapeutic strategies in oncology.
