[Mahuang (herbaceous stem of Ephedra spp.): chemistry, pharmacodynamics, and pharmacokinetics].

The Chinese medicinal herb Mahuang is herbaceous stem of Ephedra sinica, E. intermedia, or E. equisetina(Family, Ephedraceae). In China, Mahuang has been used, all the way over a millennium, as a key component herb of many herbal medicines for management of epidemics of acute respiratory illness and is also used in officially recommended herbal medicines for COVID-19. Mahuang is the first-line medicinal herb for cold and wheezing and also an effective diuretic herb for edema. However, Mahuang can also exert significant adverse effects. The key to safety and effectiveness is rational and precise use of the herb. In this review article, we comprehensively summarize chemical composition of Mahuang and associated differences in pharmacognosy, pharmacodynamics and pharmacokinetics of Mahuang compounds, along with the adverse effects of Mahuang compounds and products. Based on full understanding of how Mahuang is used in Chinese traditional medicine, systematic research on Mahuang in line with contemporary standards of pharmaceutical sciences will facilitate promoting Chinese herbal medicines to become more efficient in management of epidemic illnesses, such as COVID-19. To this end, we recommend research on Mahuang of two aspects, i.e., pharmacological investigation for its multicompound-involved therapeutic effects and toxicological investigation for clinical manifestation of the adverse effects, chemicals responsible for the adverse effects, and conditions for safe use of the herb and the herb-containing medicines.

Molecular Basis Underlying Hepatobiliary and Renal Excretion of Phenolic Acids of Salvia miltiorrhiza Roots (Danshen).

Phenolic acids are cardiovascular constituents (originating from the Chinese medicinal herb Salvia miltiorrhiza root/Danshen) of DanHong and many other Danshen-containing injections. Our earlier pharmacokinetic investigation of DanHong suggested that hepatic and/or renal uptake of the Danshen compounds was the crucial steps in their systemic elimination. This investigation was designed to survey the molecular basis underlying hepatobiliary and renal excretion of the Danshen compounds, i.e., protocatechuic acid, tanshinol, rosmarinic acid, salvianolic acid D, salvianolic acid A, lithospermic acid, and salvianolic acid B. A large battery of human hepatic and renal transporters were screened for transporting the Danshen compounds and then characterized for the uptake kinetics and also compared with associated rat transporters. The samples were analyzed by liquid chromatography/mass spectrometry. Because the Danshen phenolic acids are of poor or fairly good membrane permeability, their elimination via the liver or kidneys necessitates transporter-mediated hepatic or renal uptake from blood. Several human transporters were found to mediate hepatic and/or renal uptake of the Danshen compounds in a compound-molecular-mass-related manner. Lithospermic acid and salvianolic acid B (both >500 Da) underwent systemic elimination, initiated by organic anion-transporting polypeptide (OATP)1B1/OATP1B3-mediated hepatic uptake. Rosmarinic acid and salvianolic acids D (350-450 Da) underwent systemic elimination, initiated by OATP1B1/OATP1B3/organic anion transporter (OAT)2-mediated hepatic uptake and by OAT1/OAT2-mediated renal uptake. Protocatechuic acid and tanshinol (both <200 Da) underwent systemic elimination, initiated by OAT1/OAT2-mediated renal uptake and OAT2-mediated hepatic uptake. A similar scenario was observed with the rat orthologs. The investigation findings advance our understanding of the disposition of the Danshen phenolic acids and could facilitate pharmacokinetic research on other Danshen-containing injections.

Nanomedicines for combating multidrug resistance of cancer.

Chemotherapy typically involves the use of specific chemodrugs to inhibit the proliferation of cancer cells, but the frequent emergence of a variety of multidrug-resistant cancer cells poses a tremendous threat to our combat against cancer. The fundamental causes of multidrug resistance (MDR) have been studied for decades, and can be generally classified into two types: one is associated with the activation of diverse drug efflux pumps, which are responsible for translocating intracellular drug molecules out of the cells; the other is linked with some non-efflux pump-related mechanisms, such as antiapoptotic defense, enhanced DNA repair ability, and powerful antioxidant systems. To overcome MDR, intense efforts have been made to develop synergistic therapeutic strategies by introducing MDR inhibitors or combining chemotherapy with other therapeutic modalities, such as phototherapy, gene therapy, and gas therapy, in the hope that the drug-resistant cells can be sensitized toward chemotherapeutics. In particular, nanotechnology-based drug delivery platforms have shown the potential to integrate multiple therapeutic agents into one system. In this review, the focus was on the recent development of nanostrategies aiming to enhance the efficiency of chemotherapy and overcome the MDR of cancer in a synergistic manner. Different combinatorial strategies are introduced in detail and the advantages as well as underlying mechanisms of why these strategies can counteract MDR are discussed. This review is expected to shed new light on the design of advanced nanomedicines from the angle of materials and to deepen our understanding of MDR for the development of more effective anticancer strategies. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Photosensitizer-Doped and Plasma Membrane-Responsive Liposomes for Nuclear Drug Delivery and Multidrug Resistance Reversal.

Clinically approved doxorubicin (Dox)-loaded liposomes (e.g., Doxil) guarantee good biosafety, but their insufficient nuclear delivery of Dox (<0.4%) after cellular uptake significantly hampers their final anticancer efficacy. Here, we report that simply doping protoporphyrin IX (PpIX, a commonly used hydrophobic photosensitizer) into the lipid bilayers of Dox-loaded liposomes (the resultant product is termed PpIX/Dox liposomes) is a feasible way to promote the nuclear delivery of Dox. This facile strategy relies on a unique property of PpIX-it presents considerably higher affinity for the real plasma membrane over its liposomal carrier, which drives the doped PpIX molecules to detach from the liposomes when encountering cancer cells. We demonstrate that this process can trigger the efficient release of the loaded Dox molecules and allow them to enter the nuclei of MCF-7 breast cancer cells without being trapped by lysosomes. Regarding the drug-resistant MCF-7/ADR cells, the aberrant activation of the efflux pumps in the plasma membranes expels the internalized Dox. However, we strikingly find that the robust drug resistance can be reversed upon mild laser irradiation because the photodynamic effect of PpIX disrupts the drug efflux system (e.g., P-glycoprotein) and facilitates the nuclear entry of Dox. As a proof-of-concept, this PpIX doping strategy is also applicable for enhancing the effectiveness of cisplatin-loaded liposomes against both A549 and A549/DDP lung cancer cells. In vivo experimental results prove that a single injection of PpIX/Dox liposomes completely impedes the growth of MCF-7 tumors in nude mice within 2 weeks and, in combination with laser irradiation, can synergistically ablate MCF-7/ADR tumors. Biosafety assessments reveal no significant systemic toxicity caused by PpIX/Dox liposomes. This work exemplifies a facile method to modulate the subcellular fate of liposomal drugs and may inspire the optimization of nanopharmaceuticals in the near future.

Mitochondria-acting nanomicelles for destruction of cancer cells via excessive mitophagy/autophagy-driven lethal energy depletion and phototherapy.

Mitophagy is a specific self-protective autophagic process that degrades damaged or dysfunctional mitochondria, and is generally considered to reduce the effectiveness of mitochondria-targeted therapies. Here, we report an energy depletion-based anticancer strategy by selectively activating excessive mitophagy in cancer cells. We fabricate a type of mitochondria-targeting nanomicelles via the self-assembly of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and dc-IR825 (a near-infrared cyanine dye and a photothermal agent). The TPGS/dc-IR825 nanomicelles enable mitochondrial damage in cancer cells, which, for self-protection, activate two autophagic pathways, (1) mitophagy and (2) adenosine triphosphate (ATP) shortage-triggered autophagy. However, the excessive mitophagy/autophagy activities far surpass the degradative capacity of autolysosomes, leading to the formation of micrometer-sized vacuoles and degradation blockage. Immunofluorescence staining and Western blot analysis reveal that the nanomicelle-treated cancer cells are under severe ATP shortage, which eventually causes substantial cell death. Moreover, the nanomicelles intravenously injected into tumor-bearing mice show high tumor accumulation, long tumor retention, and inhibit the tumor growth by inducing excessive mitophagy/autophagy and energy depletion in tumor cells. Additional near-infrared laser irradiation treatment further enhances the in vitro and in vivo anticancer efficiencies of the nanomicelles, due to the excellent photothermal and photodynamic effects of dc-IR825. We believe that this work highlights the important role of mitophagy/autophagy in treating cancers.

Water-Dispersible Candle Soot-Derived Carbon Nano-Onion Clusters for Imaging-Guided Photothermal Cancer Therapy.

Herein, water-dispersible carbon nano-onion clusters (CNOCs) with an average hydrodynamic size of ≈90 nm are prepared by simply sonicating candle soot in a mixture of oxidizing acid. The obtained CNOCs have high photothermal conversion efficiency (57.5%), excellent aqueous dispersibility (stable in water for more than a year without precipitation), and benign biocompatibility. After polyethylenimine (PEI) and poly(ethylene glycol) (PEG) modification, the resultant CNOCs-PEI-PEG have a high photothermal conversion efficiency (56.5%), and can realize after-wash photothermal cancer cell ablation due to their ultrahigh cellular uptake (21.3 pg/cell), which is highly beneficial for the selective ablation of cancer cells via light-triggered intracellular heat generation. More interestingly, the cellular uptake of CNOCs-PEI-PEG is so high that the internalized nanoagents can be directly observed under a microscope without fluorescent labeling. Besides, in vivo experiments reveal that CNOCs-PEI-PEG can be used for photothermal/photoacoustic dual-modal imaging-guided photothermal therapy after intravenous administration. Furthermore, CNOCs-PEI-PEG can be efficiently cleared from the mouse body within a week, ensuring their excellent long-term biosafety. To the best of the authors' knowledge, the first example of using candle soot as raw material to prepare water-dispersible onion-like carbon nanomaterials for cancer theranostics is represented herein.

Turning double hydrophilic into amphiphilic: IR825-conjugated polymeric nanomicelles for near-infrared fluorescence imaging-guided photothermal cancer therapy.

Developing biocompatible and photodegradable photothermal agents (PTAs) holds great promise for potential clinical applications in photothermal cancer therapy. Herein, a new PTA was innovatively constructed by conjugating the hydrophobic near-infrared (NIR) heptamethine cyanine molecule IR825-NH2 with a double hydrophilic block copolymer methoxypoly(ethylene glycol)5k-block-poly(l-aspartic acid sodium salt)10 (abbreviated as PEG-PLD) via amine-carboxyl reaction. The as-designed PEG-PLD(IR825) was amphiphilic and could self-assemble into polymeric nanomicelles in aqueous solutions. Benefiting from the chemical conjugation strategy, PEG-PLD(IR825) nanomicelles realized a considerably high drug loading rate (∼21.0%) and substantially avoided the premature release of IR825 during systemic circulation. Confocal imaging revealed that the nanomicelles mainly located at mitochondria and endoplasmic reticulum after cellular internalization. In vitro photothermal therapy demonstrated the excellent cancer killing efficiency of PEG-PLD(IR825) nanomicelles due to their high light-to-heat conversion efficiency upon NIR laser irradiation. In addition, PEG-PLD(IR825) nanomicelles showed polarity-sensitive fluorescence at ∼610 nm (under 552 nm excitation) and 830 nm (under 780 nm excitation), which was especially useful for both in vitro visible fluorescence imaging and in vivo near-infrared fluorescence imaging-guided photothermal therapy (PTT). At the in vivo level, PEG-PLD(IR825) nanomicelles exhibited an excellent tumor-homing ability and a long retention time in tumor tissues as evidenced by the in vivo fluorescence imaging results. The desirable properties of PEG-PLD(IR825) nanomicelles ensured their effective tumor ablation during PTT treatment. More importantly, the PEG-PLD(IR825) nanomicelles underwent degradation after laser irradiation, which ensured their post-treatment biosafety. Therefore, the nanomicelles are promising to serve as an efficient and safe PTA for imaging-guided photothermal cancer therapy.