Tumor Microenvironment-Sensitive Liposomes Penetrate Tumor Tissue via Attenuated Interaction of the Extracellular Matrix and Tumor Cells and Accompanying Actin Depolymerization.

Delivery of anticancer drugs into tumor cores comprised of malignant cancer cells can result in potent therapeutic effects. However, conventional nanoparticle-based drug delivery systems used for cancer therapy often exhibit inefficient tumor-penetrating properties, thus, suggesting the need to improve the functional design of such systems. Herein, we focus on the interactions between cancer cells and the extracellular matrix (ECM) and demonstrate that liposomes modified with slightly acidic pH-sensitive peptide (SAPSp-lipo) can penetrate in vivo tumor tissue and in vitro spheroids comprised of cancer cells and ECM. We previously reported SAPSp-lipo, tumor microenvironment-sensitive liposomes, are effectively delivered to tumor tissue (Hama et al. J Control Release 2015, 206, 67-74). Compared with conventional liposomes, SAPSp-lipo could be delivered to deeper regions within both spheroids and tumor tissues. Furthermore, tumor penetration was found to be promoted at regions where actin depolymerization was induced by SAPSp-lipo and inhibited by the polymerization of actin. In addition, SAPSp-lipo attenuated the interaction between cancer cells and ECM, contributing to the penetration of SAPSp-lipo. These results suggest that SAPSp-lipo penetrates tumors via the interspace route and is accompanied by actin depolymerization. Taken together, SAPSp-lipo demonstrates potential as a novel tumor-penetrable drug carrier for induction of therapeutic effects against malignant cells that comprise tumor cores.

Overcoming the polyethylene glycol dilemma via pathological environment-sensitive change of the surface property of nanoparticles for cellular entry.

Modification with polyethylene glycol (PEG) is currently considered an important strategy for anti-cancer drug delivery, because PEGylated-nanoparticles would be effectively delivered to tumor tissue by enhanced permeation and retention effects. However, PEGylation suppresses the cellular uptake of nanoparticles (NPs) to target cells (known as the PEG dilemma). Here, we propose a novel strategy, namely conferring a pathological environment-sensitive property of nanoparticles for overcoming the PEG dilemma. Specifically, although nanoparticles have an overall negative surface charge to avoid interactions with biogenic substances in blood circulation, inversion of surface charge (to positive) at the pH of the tumor microenvironment may allow the nanoparticles to be taken up by cancer cells. To prove this concept, charge-invertible nanoparticles modified with novel slightly acidic pH-sensitive peptide (SAPSP-NPs) were developed. The negatively-charged SAPSP-NPs were delivered to tumor tissue, and were successfully taken up by cancer cells upon inversion of the surface charge to positive at intratumoral pH. SAPSP-NPs may serve as an alternative carrier to the PEGylated NP for anti-cancer drug delivery.

Development of a novel drug delivery system consisting of an antitumor agent tocopheryl succinate.

We have developed a novel drug delivery system (DDS) using an antitumor agent, α-tocopheryl succinate (TS). TS has attracted attention as a unique anti-cancer drug for its ability to induce apoptosis in various cancer cells. Furthermore, TS itself readily forms nanovesicles (TS-NVs) and is a prospective tool for use as an antitumor DDS. However, TS-NVs are unstable for encapsulating drugs and passive targeting delivery to tumor tissue via enhanced permeation and retention effect. Therefore, to improve the stability of vesicles, we developed a novel nanovesicle consisting of TS and egg phosphatidylcholine (TS-EPC-NVs). The stability of vesicles of TS-EPC-NVs was significantly higher than that of TS-NVs. As a result, the in vivo antitumor activity of TS-EPC-NVs was more potent than that of TS-NVs. The enhanced antitumor activity of TS-EPC-NVs was found to be due to its effective intratumoral distribution. Moreover, the in vitro anticancer efficiency of TS-EPC-NVs increased seven-fold. We suggest that the improvement is due to homogenous cellular uptake and enhanced cytosolic delivery of the nanovesicles via alteration of intracellular trafficking. Furthermore, TS-EPC-NVs encapsulating siRNA showed significant knockdown efficiency. In summary, TS-EPC-NVs represent a novel and attractive drug delivery system. The system shows antitumor activity of the encapsulated drug and the carrier itself.

Effects of co-administration of tea epigallocatechin-3-gallate (EGCG) and caffeine on absorption and metabolism of EGCG in humans.

Based on the ratios of (-)-epigallocatechin-3-gallate (EGCG) and caffeine (CAF) levels found in commercial tea drinks, EGCG and CAF were co-administered to human volunteers at various EGCG/CAF ratios, and plasma EGCG was determined by high performance liquid chromatography with chemiluminescence detection. As for the results, in plasma taken after ingestion of a beverage containing 95 mg of EGCG alone, the area under the plasma EGCG concentration-time curve (AUC) was 857 ngxh/ml. A higher AUC (1,370 ngxh/ml) was observed when subjects ingested a beverage containing EGCG (95 mg) and a low amount of CAF (40 mg). In the case of ingestion of a beverage containing EGCG (95 mg) and a high amount of CAF (180 mg), the AUC tended to be somewhat higher (1,165 ngxh/ml), but not significantly so, compared with the beverage with EGCG alone. These findings (modulation of plasma EGCG level by CAF) provide ideas for modulating the bioavailability of tea catechins, which can be applied to tea-related drinks and foods.

Fusicocca-3(16),10(14)-diene, and beta- and delta-araneosenes, new fusicoccin biosynthesis-related diterpene hydrocarbons from Phomopsis amygdali.

Further isolation and examination of fusicoccane hydrocarbons biosynthetically related to fusicoccin from Phomopsis amygdali allowed us to identify new fungal diterpene hydrocarbons of fusicoccadiene and araneosene. These were assigned as (+)-fusicocca-3(16),10(14)-diene, and (+)-beta- and (+)-delta-araneosenes. These findings led to the experimental clarification of the structures of the biosynthetic hydrocarbon intermediates presumed earlier.