Externally triggered smart drug delivery system encapsulating idarubicin shows superior kinetics and enhances tumoral drug uptake and response

Abstract

Rationale: Increasing the bioavailable drug level in a tumor is the key to enhance efficacy of chemotherapy. Thermosensitive smart drug delivery systems (SDDS) in combination with local hyperthermia facilitate high local drug levels, thus improving uptake in the tumor. However, inability to rapidly and efficiently absorb the locally released drug results in reduced efficacy, as well as undesired redistribution of the drug away from the tumor to the system. Methods: Based on this paradigm we propose a novel approach in which we replaced doxorubicin (DXR), one of the classic drugs for nanocarrier-based delivery, with idarubicin (IDA), a hydrophobic anthracycline used solely in the free form for treatment hematologic cancers. We established a series of in vitro and in vivo experiments to in depth study the kinetics of SDDS-based delivery, drug release, intratumor biodistribution and subsequent cell uptake. Results: We demonstrate that IDA is taken up over 10 times more rapidly by cancer cells than DXR in vitro . Similar trend is observed in in vivo online imaging and less drug redistribution is shown for IDA, together resulting in 4-times higher whole tumor drug uptake for IDA vs. DXR. Together his yielded an improved intratumoral drug distribution for IDA-SDDS, translating into superior tumor response compared to DXR-SDDS treatment at the same dose. Thus, IDA - a drug that is not used for treatment of solid cancers - shows superior therapeutic index and better outcome when administered in externally triggered SDDS. Conclusions: We show that a shift in selection of chemotherapeutics is urgently needed, away from the classic drugs towards selection based on properties of a chemotherapeutic in context of the nanoparticle and delivery mode, to maximize the therapeutic efficacy.

Active Interphase Enables Stable Performance for an All‐Phosphate‐Based Composite Cathode in an All‐Solid‐State Battery

“…This is attributed to the sluggish Li + diffusion because of the reduced number of free Li + vacancy/interstitial sites at the fully charged state. [ 75,76 ] Experimentally, it is also discovered that the total resistance of the cell that discharged to 2.2 V after ten cycles (≈450 Ω) is higher than those of the cells with discharge cut‐off voltages at 2.8 and 2.5 V (≈300 Ω) (Figure 4b,d,f). As delithiation proceeds, the freeing up of partial Li + sites in LFTAP and LATP may positively affect the Li + transport kinetic.…”

Constructing Interfacial Nanolayer Stabilizes 4.3 V High‐Voltage All‐Solid‐State Lithium Batteries with PEO‐Based Solid‐State Electrolyte

“…Generally, there exist the polarization in the ASSLBs during charging, accompanied with an overpotential after charge due to the aforementioned interfacial problems. [ 13 ] A rest step is in favor of the release of the polarization. [ 14 ] In practical applications (such as portable electronics and electric vehicles), batteries are unlikely to be continuous operation without rest.…”

Extracorporeal Removal of Thermosensitive Liposomal Doxorubicin from Systemic Circulation after Tumor Delivery to Reduce Toxicities

“…Due to the complexity of the procedure, DFPP takes around 4–6 h to complete. DFPP is therefore not suitable for most TSL-Dox formulations which typically have a plasma half-life of only 1–2 h [ 18 , 24 , 30 , 31 , 32 , 33 , 34 ]. Unencapsulated Dox, on the other hand, can be removed very rapidly by activated carbon filters.…”