Glutathione-responsive PLGA nanocomplex for dual delivery of doxorubicin and curcumin to overcome tumor multidrug resistance

Aim: This work aims to develop an injectable nano-drug delivery system to overcome tumor multidrug resistance (MDR). Methods: A drug delivery nanoplatform based on PEGylated PLGA with glutathione (GSH) responsivity was constructed for dual delivery of doxorubicin and curcumin (termed DCNP), and its MDR reversal efficiency was studied in vitro and in vivo. Results: The DCNPs exhibited a rapid drug release profile under high GSH concentration and could enhance the cellular uptake and cytotoxicity of doxorubicin to MDR cancer cells. Moreover, the DCNPs showed better biocompatibility, longer blood circulation and enhanced antitumor efficiency compared with free drugs. Conclusion: The GSH-responsive nanocarrier is believed to be a promising candidate for overcoming tumor MDR.

Synergistic Therapy of Doxorubicin with Cationic Anticancer Peptide L-K6 Reverses Multidrug Resistance in Cancer Cells in vitro via P-glycoprotein Inhibition

Multidrug resistance (MDR) is one of the major obstacles to efficient chemotherapy against cancers, resulting from the overexpression of drug efflux transporters such as P-glycoprotein (P-gP). In the present study, we aimed to evaluate the MDR reversal activity and synergistic therapeutic potential of cationic anticancer peptide L-K6 with doxorubicin (DOX) on P-gP-overexpressing and DOX-resistant MCF-7/Adr human breast cancer cells. Flow cytometry and confocal laser scanning microscopy were used to determine the intracellular accumulation of DOX and another P-gP substrate, Rho123. P-gP-Glo assay, Western blot and Biacore analysis were further performed to evaluate the P-gP function and expression. The cytotoxicity in MCF-7 or MCF-7/Adr cells was measured by MTT assay. Flow cytometry assay and confocal laser scanning microscopy observation clearly revealed an increased intracellular accumulation of DOX and Rho123 in MCF-7/Adr cells treated with L-K6, suggesting a P-gP inhibiting potential. Biacore analysis, P-gP-Glo assay and Western blot further confirmed that L-K6 could directly interact with P-gP, inhibit P-gP function and decrease P-gP expression in MCF-7/Adr cells. In addition, as expected, the data from MTT assay indicated that L-K6 restored the sensitivity of MCF-7/Adr cells to DOX, indicating a MDR reversal potential and a promising synergistic anticancer activity. All these findings may provide experimental evidence to support the promising applications and synergistic therapeutic potential of peptidic P-gP inhibitors against MDR cancer.

Two new seco-polycyclic polyprenylated acylphloroglucinol from Hypericum sampsonii

Two rare seco-polycyclic polyprenylated acylphloroglucinols (1 and 2) were isolated from Hypericum sampsonii. Compounds 1 and 2 showed moderate multidrug resistance (MDR) reversal activity to resistant cancer cells, HepG2/ADR and MCF-7/ADR.

Chemosensitizing micelles self-assembled from amphiphilic TPGS-indomethacin twin drug for significantly synergetic multidrug resistance reversal

Vitamin E d-ɑ-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS) and indomethacin (IDM) can reverse multidrug resistance (MDR) via inhibiting P-glycoprotein (P-gp) and multidrug resistance associated protein 1 (MRP1) respectively, but their drawbacks in physicochemical properties limit their clinical application. To overcome these defects and enhance MDR reversal, the amphiphilic TPGS-IDM twin drug was successfully synthesized via esterification, and could self-assemble into free and paclitaxel-loaded (PTX-loaded) micelles. The micelles exhibited lower CMC values (5.2 × 10−5 mg/mL), long-term stability in PBS (pH 7.4) for 7 days and SDS solution (5 mg/mL) for 3 days, and effective drug release at esterase/pH 5.0. Moreover, the micelles could down-regulate ATP levels and promote ROS production in MCF-7/ADR via the mitochondrial impairment, therefore achieving MDR reversal and cell apoptosis. Additionally, the PTX-loaded micelles could significantly inhibit the cell proliferation and promote apoptosis for MCF-7/ADR via the synergistic chemosensitizing effect of TPGS and IDM, and synergistic cytotoxic effect of TPGS and PTX. Thus, the chemosensitizing micelles self-assembled from amphiphilic TPGS-indomethacin twin drug have the great potentials for reversing MDR in clinical cancer therapy.

Functionalized Carbon Nanostructures Versus Drug Resistance: Promising Scenarios in Cancer Treatment

Carbon nanostructures (CN) are emerging valuable materials for the assembly of highly engineered multifunctional nanovehicles for cancer therapy, in particular for counteracting the insurgence of multi-drug resistance (MDR). In this regard, carbon nanotubes (CNT), graphene oxide (GO), and fullerenes (F) have been proposed as promising materials due to their superior physical, chemical, and biological features. The possibility to easily modify their surface, conferring tailored properties, allows different CN derivatives to be synthesized. Although many studies have explored this topic, a comprehensive review evaluating the beneficial use of functionalized CNT vs G or F is still missing. Within this paper, the most relevant examples of CN-based nanosystems proposed for MDR reversal are reviewed, taking into consideration the functionalization routes, as well as the biological mechanisms involved and the possible toxicity concerns. The main aim is to understand which functional CN represents the most promising strategy to be further investigated for overcoming MDR in cancer.

Dual P-Glycoprotein and CA XII Inhibitors: A New Strategy to Reverse the P-gp Mediated Multidrug Resistance (MDR) in Cancer Cells

A new series of N,N-bis(alkanol)amine aryl diesters was synthesized and studied as dual P-glycoprotein (P-gp) and carbonic anhydrase XII inhibitors (CA XII). These hybrids should be able to synergistically overcome P-gp mediated multidrug resistance (MDR) in cancer cells. It was reported that the efflux activity of P-gp could be modulated by CA XII, as the pH reduction caused by CA XII inhibition produces a significant decrease in P-gp ATPase activity. The new compounds reported here feature both P-gp and CA XII binding moieties. These hybrids contain a N,N-bis(alkanol)amine diester scaffold found in P-glycoprotein ligands and a coumarin or benzene sulfonamide moiety to target CA XII. Many compounds displayed a dual activity against P-gp and CA XII being active in the Rhd 123 uptake test on K562/DOX cells and in the hCA XII inhibition test. On LoVo/DOX cells, that overexpress both P-gp and CA XII, some coumarin derivatives showed a high MDR reversal effect in Rhd 123 uptake and doxorubicin cytotoxicity enhancement tests. In particular, compounds 7 and 8 showed higher activity than verapamil and were more potent on LoVo/DOX than on K562/DOX cells overexpressing only P-gp. They can be considered as valuable candidates for selective P-gp/CA XII inhibition in MDR cancer cells.