Latest ArticlesOxaliplatin (Oxa) is the first-line chemotherapeutic drug for the treatment of colorectal cancer (CRC). However, long-term Oxa chemotherapy can induce inflammation and increase the levels of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2), which can promote tumor metastasis. Moreover, high glutathione (GSH) levels in CRC cells significantly reduce Oxa sensitivity and seriously restrict the clinical application of Oxa. Herein, an Oxa(Ⅳ) prodrug with anti-inflammatory properties (desmethyl naproxe, DN) and GSH-depleting cyclodextrin pseudo-polyrotaxane carriers were prepared and further self-assembled into micellar nanoparticles (designated DNPt@PPRI). The relesae of DN from DNPt@PPRI can reduce the level of PGE2 to inhibit inflammation and tumor metastasis by decreasing COX-2 protein, and also synergize with Oxa to inhibit tumor. More importantly, GSH depletion can reduce the detoxification of Oxa and further enhance chemotherapy-induced apoptosis. DNPt@PPRI have a good GSH depletion ability to enhance the sensitivity of Oxa, indicating a potential in the synergistic chemotherapy and chemo-sensitization of colorectal cancer.
Lipid-based nanocarriers have staged a remarkable comeback in the oral delivery of proteins and peptides, but delivery efficiency is compromised by lipolysis. β-Lactoglobulin (β-lg) stabilized lipid nanoparticles, including nanoemulsions (NE@β-lg) and nanocapsules (NC@β-lg), were developed to enhance the oral absorption of insulin by slowing down lipolysis due to the protection from β-lg. Cremophor EL stabilized nanoemulsions (NE@Cre-EL) were prepared and set as a control. The lipid nanoparticles produced mild and sustained hypoglycemic effects, amounting to oral bioavailability of 3.0% ± 0.3%, 7.0% ± 1.1%, and 7.7% ± 0.8% for NE@Cre-EL, NE@β-lg, and NC@β-lg, respectively. Aggregation-caused quenching (ACQ) probes enabled the identification of intact nanoparticles, which were used to investigate the in vivo and intracellular fates of the lipid nanoparticles. In vitro digestion/lipolysis and ex vivo imaging confirmed delayed lipolysis from β-lg stabilized lipid nanoparticles. NC@β-lg was more resistant to intestinal lipolysis than NE@β-lg due to the Ca2+-induced crosslinking. Live imaging revealed the transepithelial transport of intact nanoparticles and their accumulation in the liver. Cellular studies confirmed the uptake of intact nanoparticles. Slowing down lipolysis via food proteins represents a good strategy to enhance the oral absorption of lipid nanoparticles and thus co-formulated biomacromolecules.
Photoacoustic agents combining photodynamic therapy (PDT) and photothermal therapy (PTT) functions have emerged as potent theranostic agents for combating cancer. The molecular approaches for enhancing the near-infrared (NIR)-absorption and maximizing non-radiative energy transfer are essential for effective photoacoustic imaging (PAI) and therapy applications. In addition, such molecules with high specificity and affinity to cancer cells are urgently needed, which would further decrease the side effect during treatments. In this study, we applied a heavy-atom engineering strategy and introduced p-aminophenol, -thio, and -seleno moieties into NIR heptamethine cyanine (Cy7) skeleton (Cy7-X-NH2, X = O, S, Se) to significantly increase photothermal conversion efficiency for PTT and promote intersystem crossing for PDT. Additionally, we designed a series of nitroreductase (NTR)-activated photoacoustic probes (Cy7-X-NO2, X = O, S, Se), and target hypoxic tumors with NTR overexpression. Our prostate cancer targeting probe, Cy7-Se-NO2-KUE, exhibited specific tumor photoacoustic signals and effective tumor killing through outstanding synergistic PTT/PDT in vivo. These findings highlighted a versatile strategy for cancer photoacoustic diagnosis and enhanced phototherapy.
Peptide-drug conjugates have achieved considerable development and application as a novel strategy for targeted delivery of anticancer drugs. Bioactive peptides induced calcium deposition can irreversibly assist inhibition of tumors. However, active regulation of calcium level through signal transduction of bioactive substances has not been reported yet. In this study, novel neuropeptide-doxorubicin conjugates (NP-DOX) with lysosome-specific acid response were described for neuropeptide Y1 receptor (Y1R)-overexpressed triple-negative breast cancer. The delivery mechanism of NP-DOX was clarified that diverse pathways were involved, including intracellular and intercellular transport. Importantly, up-regulation of Y1R-mediated intracellular calcium level via second messenger inositol triphosphate was presented in NP-DOX treated MDA-MB-231 cells. In vivo antitumor efficacy demonstrated that NP-DOX showed less organ toxicity and enhanced tumor inhibition benefited from its controlled release and Y1R-mediated calcium deposition, compared with free DOX. This bioconjugate is a proof-of-concept confirming that neuropeptide-mediated control of signaling responses in neuropeptide-drug conjugates enables great potential for further applications in tumor chemotherapy.
Mesoporous titanium nanoparticles (MTNs) have emerged as an important porous semiconductor owning to their large surface area and unique electronic/optical properties. However, the fundamental research for rational manufacturing MTNs in a highly scalable manner remains a challenge. In this study, we report a two-step flash nanocomplexation (FNC) approach to large-scalable generate MTNs through the sequential combination of two multi-inlet vortex mixers. By optimizing the concentrated titanium precursor, polyethylene glycol (PEG)-functionalized silane amount and pH, we have been able to produce MTNs with small particle size (31.5 nm), larger surface area (416.9 m²/g) and pore volume (0.59 cm3/g). Different from the traditional MTNs bulk, FNC-produced MTNs exhibited well-controlled manner and exceptional photocatalytic and antibacterial properties. Importantly, the optimized MTNs outperformed commercial P25 not only in protecting ultraviolet A (UVA)-exposed skin, but also in treating P. aeruginosa-infected wound. We believe that the high controllability and scalability of sequential flash nanocomplexation method offers great opportunities in enhancing the performance of mesoporous titanium nanoparticles.
Lidocaine hydrochloride (LIDH) as an anesthetic is widely used in local anesthesia. Dissolving microneedles (MNs) have great application value in the field of skin anesthesia. However, the limited drug-loading of dissolving MNs is an existing challenge that affects clinical use. In this study, we have screened isomaltulose (ISO) as the proper matrix material for the MNs by using molecular dynamics (MD) simulation. Our findings indicate that ISO has good compatibility with LIDH, and the LIDH-loaded ISO MNs (LI-MNs) have high drug-loading capacity. The drug-loading capacity of LI-MNs could reach 80%, and it could effectively puncture the skin. In addition, the preparation method of customized LI-MNs was established based on three-dimensional (3D) printing technology. It was shown that the administration time of LI-MNs could be controlled within 3 min. Also, the LI-MNs were able to provide the local anesthetic efficacy within 2 min and sustained for more than 2 h. Significantly, LI-MNs had more efficient drug efficacy compared to the topical creams and the majority of existing LIDH-loaded dissolving MNs. They even provided a longer duration of action than the injections. Overall, the LI-MNs with high drug-loading have a promising application prospect.
Liposomes are one of the significant classes of antitumor nanomaterials and the most successful nanomedicine drugs in clinical translation. However, it is difficult to accurately reveal liposome delivery modes and drug release rates at different pH values to assess the biodistribution and drug delivery pathways in vivo. Here, we established a strategy to integrate Bi-doped carbon quantum dots (CQDs) with liposomes to produce fluorescence visualization and therapeutic effects, namely lipo/Bi-doped CQDs. Lipo/Bi-doped CQDs show good water solubility and physicochemical properties, which can be used for in vitro labeling of colon cancer (CT26) cells and in vivo imaging localization tracking tumors for monitoring. Simultaneously, thanks to the excellent pH sensitivity and ion doping characteristic of Bi-doped CQDs, lipo/Bi-doped CQDs can be used to reveal the drug release rate of liposomes at different pH values and exhibit potential effects in vivo antitumor therapy.
Unspecific peroxygenases (UPOs, EC 1.11.2.1) is a kind of thioheme enzyme capable of catalyzing various oxidations of inert C–H bonds using H2O2 as an oxygen donor without cofactors. However, the enhancement of the H2O2 tolerance of UPOs is always challenging. In this study, the A161C mutant of rDcaUPO, which originates from Daldinia caldariorum, was found to be highly H2O2-resistant. Compared with the wild type, the mutant rDcaUPO-A161C showed a 10-h prolonged half-life and a 64% improved enzyme activity when incubated in 10 mmol/L H2O2. The crystal structure analysis at 1.47 Å showed that rDcaUPO-A161C exhibited 10 α-helixes (cyan) and a series of ordered rings, forming a single asymmetric spherical structure. The two conserved domains near heme formed an active site with the catalytic PCP and EHD regions (Glu86, His87, Asp88 residues). The H2O2 tolerance of rDcaUPO-A161C was preliminarily explored by comparing its structure with the wild type. Notably, rDcaUPO-A161C showed significantly higher catalytic efficiency than the wild type for the production of hydroxyl fatty acids. This study is anticipated to provide an insight into the structure-function relationship and expand potential applications of UPOs.
Erlotinib is an orally administered, highly effective, specific epidermal growth factor receptor tyrosine kinase inhibitor, used to treat non-small cell lung cancer and pancreatic cancer. The traditional synthetic methods for Erlotinib exhibit long reaction time and safety concern. Herein, we describe a novel five-step route for the synthesis of Erlotinib in flow. These five steps comprise etherification, nitration, reduction, addition and cyclization reactions. All steps were optimized and converted to continuous flow process, which drastically reduces the reaction time and considerably improves the process safety as well as the total yield. Enabled by five continuous flow units, Erlotinib is efficiently afforded with an E-factor of 38, an overall yield of 83%, and a total residence time of 25.1 min. Majority steps in this process have been optimized for quantitative conversion, which offers the possibility of telescoping the entire process.
One of the largest subfamilies within the famous Daphniphyllum alkaloid family is made up of the yuzurimine-type (or macrodaphniphyllamine-type) alkaloids. Their complex aza-polycyclic caged structures, several contiguous stereogenic centers, and vicinal all-carbon quaternary centers make these alkaloids formidable challenge for synthetic chemists. Recently, synthesis of these alkaloids has received extensive attention from our community. Herein, we wish to report the total synthesis of C14–epi-deoxycalyciphylline H, a putative member of yuzurimine-type alkaloid subfamily. Key transformations employed in our approach include an intramolecular Prins reaction and a Pd-catalyzed enyne cycloisomerization. In addition, synthesis of a daphnezomine L-type alkaloid, paxdaphnidine A, was also studied.
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