Scalable electrosynthesis of commodity chemicals from biomass by suppressing non-Faradaic transformations.

Electrooxidation of biomass platforms provides a sustainable route to produce valuable oxygenates, but the practical implementation is hampered by the severe carbon loss stemming from inherent instability of substrates and/or intermediates in alkaline electrolyte, especially under high concentration. Herein, based on the understanding of non-Faradaic degradation, we develop a single-pass continuous flow reactor (SPCFR) system with high ratio of electrode-area/electrolyte-volume, short duration time of substrates in the reactor, and separate feeding of substrate and alkaline solution, thus largely suppressing non-Faradaic degradation. By constructing a nine-stacked-modules SPCFR system, we achieve electrooxidation of glucose-to-formate and 5-hydroxymethylfurfural (HMF)-to-2,5-furandicarboxylic acid (FDCA) with high single-pass conversion efficiency (SPCE; 81.8% and 95.8%, respectively) and high selectivity (formate: 76.5%, FDCA: 96.9%) at high concentrations (formate: 562.8 mM, FDCA: 556.9 mM). Furthermore, we demonstrate continuous and kilogram-scale electrosynthesis of potassium diformate (0.7 kg) from wood and soybean oil, and FDCA (1.17 kg) from HMF. This work highlights the importance of understanding and suppressing non-Faradaic degradation, providing opportunities for scalable biomass upgrading using electrochemical technology.

A stabilized peptide ligand for multifunctional glioma targeted drug delivery.

Peptide ligands consisting of l-amino acids are subject to proteolysis in vivo. When modified on the surface of nanocarriers, those peptide ligands would readily degrade and the targeting efficacy is significantly attenuated. It has received increasing scrutiny to design stable peptide ligands for targeted drug delivery. Here, we present the design of a stable peptide ligand by the formation of a head-to-tail amide bond as an example. Even though the linear l-peptide A7R (termed LA7R) can bind specifically to vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1) that are overexpressed on glioma cells, neovasculature and glioma vasculogenic mimicry (VM), the tumor-homing capacity of LA7R is greatly impaired in vivo due to proteolysis (e.g. in the serum). A cyclic A7R (cA7R) peptide was identified by computer-aided peptide design and synthesized with high yield by combining solid phase peptide synthesis and native chemical ligation. The binding of cA7R to both receptors was theoretically and experimentally assessed. In our simulated model hydrophobic and ionic interactions dominated the binding of LA7R to receptors. It is very interesting that cA7R adopting a different structure from LA7R retained high binding affinities to receptors without affecting the hydrophobic and ionic interactions. After head-to-tail cyclization by the formation of an amide bond, cA7R exhibited exceptional stability in mouse serum. Either cA7R or LA7R was conjugated on the surface of doxorubicin (DOX) loaded liposomes (cA7R-LS/DOX or LA7R-LS/DOX). The results of in vitro cellular assays indicated that cA7R-LS/DOX not only displayed stronger anti-proliferative effect against glioma cells, but also demonstrated to be more efficient in destruction of VM and HUVEC tubes in comparison to LA7R-LS/DOX and plain liposomes (LS/DOX, without peptide conjugation). cA7R conjugation could achieve significantly higher accumulation of liposomes in glioma than did LA7R conjugation, which in turn, cA7R-LS/DOX could substantially suppress subcutaneous tumor growth when compared with other DOX formulations (free DOX, LS/DOX and LA7R-LS/DOX). The designed cyclic A7R exhibited the capability of targeting glioma cells, neovasculature and VM simultaneously in vivo. Considering the ease of synthesis, high binding affinity to receptors and increased stability of cA7R peptide in the present study, the design of head-to-tail cyclized peptides by the formation of amide bond based on computer-aided peptide design presents an alternative method to identify proteolytically stable peptide ligands.

Stabilized Heptapeptide A7R for Enhanced Multifunctional Liposome-Based Tumor-Targeted Drug Delivery.

(L)A7R (ATWLPPR) is a heptapeptide with high binding affinity in vitro to vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1) overexpressed on glioma, glioma vasculogenic mimicry and neovasculature. However, its tumor targeting efficacy is significantly reduced in vivo due to proteolysis in blood circulation. To improve the in vivo stability and targeting efficacy, the retro inverso isomer of (L)A7R ((D)A7R) was developed for glioma-targeted drug delivery. (D)A7R was expected to have a similar binding affinity to its receptors in vitro (VEGFR2 and NRP-1), which was experimentally confirmed. In vivo, (D)A7R-modified liposomes achieved improved glioma-targeted efficiency than did (L)A7R-modified liposomes. After loading a chemotherapeutic agent (doxorubicin), (D)A7R-modified liposomes significantly inhibited subcutaneous model tumor in comparison to free doxorubicin, plain liposomes and (L)A7R-modified liposomes. In summary, the present study presented the potential of a proteolytically stable d-peptide ligand for in vivo tumor-targeted drug delivery.

Liposome-Based Systemic Glioma-Targeted Drug Delivery Enabled by All-d Peptides.

As the most aggressive brain tumor, chemotherapy of malignant glioma remains to be extremely challenging in clinic. The blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) are physiological and pathological barriers preventing therapeutic drugs from reaching the glioma region. In addition, vasculogenic mimicry (VM) formed by invasive glioma cells instead of endothelial cells and angiogenesis are very common in glioma, leading to the poor prognosis and recurrence of glioma. An ideal drug delivery system for glioma chemotherapy needs to traverse the BBB and BBTB and then target VM, angiogenesis, and glioma cells. Herein we developed a liposome-based drug delivery system with the modification of proteolytically stable d-peptide ligands (dCDX/dA7R-LS). dCDX is a d-peptide ligand of nicotine acetylcholine receptors (nAChRs) capable of circumventing the BBB, and dA7R is a d-peptide ligand of vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1) overexpressed on angiogenesis, VM, and glioma, presenting excellent glioma-homing property. dCDX/dA7R-LS could efficiently internalize into the brain capillary endothelial cells, glioma cells, tumor neovascular endothelial cells, and tumor spheroids and cross the in vitro BBB and BBTB models. Ex vivo imaging and in vivo immunofluorescence assays confirmed the superiority of dCDX/dA7R-LS in targeting intracranial glioma in comparison to plain liposomes or liposomes modified with an individual d-peptide ligand (either dCDX or dA7R). When loaded with doxorubicin, dCDX/dA7R-LS achieved the best antiglioma, antiangiogenesis, and anti-VM effects among all tested formulations. These results suggested that systemic glioma-targeted drug delivery enabled by all-d peptide ligands was promising for the antiglioma therapy.