Cancer sensitizing effect of deazaflavin analogs is associated with increased intracellular drug accumulation.

As part of our efforts geared towards developing mechanism-based cancer sensitizing agents, we have previously synthesized and characterized novel deazaflavin analogs as potent tyrosyl DNA phosphodiesterase 2 (TDP2) inhibitors for combination treatments with topoisomerase II (TOP2) poisons. Interestingly, the sensitizing effect of a few analogs toward TOP2 poison etoposide (ETP) was associated with a significant increase in intracellular drug accumulation, which could be an alternative mechanism to boost the clinical efficacy of ETP in cancer chemotherapies. Hence, we evaluated more deazaflavin TDP2 inhibitors for their impact on drug retention in cancer cells. We found that all but one tested TDP2 inhibitors substantially increased the ETP retention in DT40 cells. Particularly, we identified an exceptionally potent analog, ZW-1226, which at 3 nM increased the intracellular ETP by 13-fold. Significantly, ZW-1226 also stimulated cellular accumulation of two other anticancer drugs, TOP2 poison teniposide and antifolate pemetrexed, and produced an effect more pronounced than those of ABC transporter inhibitors verapamil and elacridar in human leukemic CCRF-CEM cells toward ETP. Lastly, ZW-1226 potentiated the action of ETP in the sensitive human CCRF-CEM cells and a few resistant non-small-cell lung cancer (NSCLC) cells, including H460 and H838 cells. Collectively, the results of this study strongly suggest that deazaflavin analog ZW-1226 could be an effective cancer sensitizing agent which warrants further investigation.

Virus-like particle-based nanocarriers as an emerging platform for drug delivery.

New nanocarrier technologies are emerging, and they have great potential for improving drug delivery, targeting efficiency and bioavailability. Virus-like particles (VLPs) are natural nanoparticles from animal and plant viruses and bacteriophages. Hence, VLPs present several great advantages, such as morphological uniformity, biocompatibility, reduced toxicity and easy functionalisation. VLPs can deliver many active ingredients to the target tissue and have great potential as a nanocarrier to overcome the limitations associated with other nanoparticles. This review will focus primarily on the construction and applications of VLPs, particularly as a novel nanocarrier to deliver active ingredients. Herein, the main methods for the construction, purification and characterisation of VLPs, as well as various VLP-based materials used in delivery systems are summarised. The biological distribution of VLPs in drug delivery, phagocyte-mediated clearance and toxicity are also discussed.

A review of existing strategies for designing long-acting parenteral formulations: Focus on underlying mechanisms, and future perspectives.

The need for long-term treatments of chronic diseases has motivated the widespread development of long-acting parenteral formulations (LAPFs) with the aim of improving drug pharmacokinetics and therapeutic efficacy. LAPFs have been proven to extend the half-life of therapeutics, as well as to improve patient adherence; consequently, this enhances the outcome of therapy positively. Over past decades, considerable progress has been made in designing effective LAPFs in both preclinical and clinical settings. Here we review the latest advances of LAPFs in preclinical and clinical stages, focusing on the strategies and underlying mechanisms for achieving long acting. Existing strategies are classified into manipulation of in vivo clearance and manipulation of drug release from delivery systems, respectively. And the current challenges and prospects of each strategy are discussed. In addition, we also briefly discuss the design principles of LAPFs and provide future perspectives of the rational design of more effective LAPFs for their further clinical translation.

A combined "eat me/don't eat me" strategy based on extracellular vesicles for anticancer nanomedicine.

A long-term and huge challenge in nanomedicine is the substantial uptake and rapid clearance mediated by the mononuclear phagocyte system (MPS), which enormously hinders the development of nanodrugs. Inspired by the natural merits of extracellular vesicles, we therefore developed a combined "eat me/don't eat me" strategy in an effort to achieve MPS escape and efficient drug delivery. Methodologically, cationized mannan-modified extracellular vesicles derived from DC2.4 cells were administered to saturate the MPS (eat me strategy). Then, nanocarriers fused to CD47-enriched exosomes originated from human serum were administered to evade phagocytosis by MPS (don't eat me strategy). The nanocarriers were also loaded with antitumor drugs and functionalized with a novel homing peptide to promote the tumour tissue accumulation and cancer cell uptake (eat me strategy). The concept was proven in vitro as evidenced by the reduced endocytosis of macrophages and enhanced uptake by tumour cells, whereas prolonged circulation time and increased tumour accumulation were demonstrated in vivo. Specially, the strategy induced a 123.53% increase in tumour distribution compared to conventional nanocarrier. The study both shed light on the challenge overcoming of phagocytic evasion and provided a strategy for significantly improving therapeutic outcomes, potentially permitting active drug delivery via targeted nanomedicines.

Regulating Interactions Between Targeted Nanocarriers and Mononuclear Phagocyte System via an Esomeprazole-Based Preconditioning Strategy.

PURPOSE: The mononuclear phagocyte system (MPS) presents a formidable obstacle that hampers the delivery of various nanopreparations to tumors. Therefore, there is an urgent need to improve the off-MPS targeting ability of nanomedicines. In the present study, we present a novel preconditioning strategy to substantially increase the circulation times and tumor targeting of nanoparticles by regulating nanocarrier-MPS interactions. METHODS: In vitro, the effect of different vacuolar H+-ATPase inhibitors on macrophage uptake of targeted or nontargeted lipid vesicles was evaluated. Specifically, the clinically approved proton-pump inhibitor esomeprazole (ESO) was selected as a preconditioning agent. Then, we further investigated the blocking effect of ESO on the macrophage endocytosis of nanocarriers. In vivo, ESO was first intravenously administered into A549-tumor-bearing nude mice, and 24 h later, the c(RGDm7)-modified vesicles co-loaded with doxorubicin and gefitinib were intravenously injected. RESULTS: In vitro, ESO was found to reduce the interactions between macrophages and c(RGDm7)-modified vesicles by interfering with the latter's lysosomal trafficking. Studies conducted in vivo confirmed that ESO pretreatment greatly decreased the liver and spleen distribution of the targeted vesicles, enhanced their tumor accumulation, and improved the therapeutic outcome of the drug-loaded nanomedicines. CONCLUSION: Our findings indicate that ESO can regulate the nanoparticle-MPS interaction, which provides a feasible option for enhancing the off-MPS targeting of nanomedicines.

Multifunctional targeted liposomal drug delivery for efficient glioblastoma treatment.

Glioblastoma multiforme (GBM) has been considered to be the most malignant brain tumors. Due to the existence of various barriers including the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) greatly hinder the accumulation and deep penetration of chemotherapeutics, the treatment of glioma remains to be the most challenging task in clinic. In order to circumvent these hurdles, we developed a multifunctional liposomal glioma-targeted drug delivery system (c(RGDyK)/pHA-LS) modified with cyclic RGD (c(RGDyK)) and p-hydroxybenzoic acid (pHA) in which c(RGDyK) could target integrin αvß3 overexpressed on the BBTB and glioma cells and pHA could target dopamine receptors on the BBB. In vitro, c(RGDyK)/pHA-LS could target glioblastoma cells (U87), brain capillary endothelial cells (bEnd.3) and umbilical vein endothelial cells (HUVECs) through a comprehensive pathway. Besides, c(RGDyK)/pHA-LS could also increase the cytotoxicity of doxorubicin encapsulated in liposomes on glioblastoma cells, and was able to penetrate inside the glioma spheroids after traversing the in vitro BBB and BBTB. In vivo, we demonstrated the targeting ability of c(RGDyK)/pHA-LS to intracranial glioma. As expected, c(RGDyK)/pHA-LS/DOX showed a median survival time of 35 days, which was 2.31-, 1.76- and 1.5-fold higher than that of LS/DOX, c(RGDyK)-LS/DOX, and pHA-LS/DOX, respectively. The findings here suggested that the multifunctional glioma-targeted drug delivery system modified with both c(RGDyK) and pHA displayed strong antiglioma efficiency in vitro and in vivo, representing a promising platform for glioma therapy.

Design of Y-shaped targeting material for liposome-based multifunctional glioblastoma-targeted drug delivery.

Since the treatment of glioma in clinic has been hindered by the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB), multifunctional glioma-targeted drug delivery systems that can circumvent both barriers have received increasing scrutiny. Despite recent research efforts have been made to develop multifunctional glioma-targeted liposomes by decorating two or more ligands, few successful trials have been achieved due to the limitation of ligand density on the surface of liposomes. In this study, we designed a Y-shaped multifunctional targeting material c(RGDyK)-pHA-PEG-DSPE, in which cyclic RGD (c(RGDyK)) and p-hydroxybenzoic acid (pHA) were linked with a short spacer. Since c(RGDyK) and pHA could respectively circumvent the BBTB and BBB, c(RGDyK)-pHA-PEG-DSPE-incorporated liposomes could achieve multifunctional glioma-targeted drug delivery with maximal density of both functional moieties. c(RGDyK)-pHA-PEG-DSPE-incorporation enhanced cellular uptake of liposomes in bEnd.3, HUVECs and U87 cells, and increased cytotoxicity of doxorubicin (DOX) loaded liposomes on glioblastoma cells. c(RGDyK)-pHA-PEG-DSPE-incorporated liposomes (c(RGDyK)-pHA-LS) could deeply penetrate the 3D glioma spheroids after crossing the BBB and BBTB models in vitro. Moreover, in vivo fluorescence imaging showed the highest tumor distribution of c(RGDyK)-pHA-LS than did plain liposomes (no ligand modification) and liposomes modified with a single ligand (either c(RGDyK) or pHA). When loaded with DOX, c(RGDyK)-pHA-LS displayed the best anti-glioma effect with a median survival time (36.5days) significantly longer than that of DOX loaded plain liposomes (26.5days) and liposomes modified with a single ligand (28.5days for RGD and 30days for pHA). These results indicated that design of Y-shaped targeting material was promising to maximize the multifunctional targeting effects of liposomes on the therapy of glioma.