Targeted Repair of Spinal Cord Injury Based on miRNA-124-3p-Loaded Mesoporous Silica Camouflaged by Stem Cell Membrane Modified with Rabies Virus Glycoprotein.

Spinal cord injury (SCI) has no effective treatment modalities. It faces a significant global therapeutical challenge, given its features of poor axon regeneration, progressive local inflammation, and inefficient systemic drug delivery due to the blood-spinal cord barrier (BSCB). To address these challenges, a new nano complex that achieves targeted drug delivery to the damaged spinal cord is proposed, which contains a mesoporous silica nanoparticle core loaded with microRNA and a cloaking layer of human umbilical cord mesenchymal stem cell membrane modified with rabies virus glycoprotein (RVG). The nano complex more readily crosses the damaged BSCB with its exosome-resembling properties, including appropriate size and a low-immunogenic cell membrane disguise and accumulates in the injury center because of RVG, where it releases abundant microRNAs to elicit axon sprouting and rehabilitate the inflammatory microenvironment. Culturing with nano complexes promotes axonal growth in neurons and M2 polarization in microglia. Furthermore, it showed that SCI mice treated with this nano complex by tail vein injection display significant improvement in axon regrowth, microenvironment regulation, and functional restoration. The efficacy and biocompatibility of the targeted delivery of microRNA by nano complexes demonstrate their immense potential as a noninvasive treatment for SCI.

Identification of recurrent BRAF non-V600 mutations in intraductal carcinoma of the prostate in Chinese populations.

While BRAF alterations have been established as a driver in various solid malignancies, the characterization of BRAF alterations in prostate cancer (PCa) has not been thoroughly interrogated. By bioinformatics analysis, we first found that BRAF alterations were associated with advanced PCa and exhibited mutually exclusive pattern with ERG alteration across multiple cohorts. Of the most interest, recurrent non-V600 BRAF mutations were found in 3 of 21 (14.3 %) PCa patients demonstrating IDC-P morphology. Furthermore, experimental overexpression of BRAFK601E and BRAFL597R exhibited emergence of oncogenic phenotypes with intensified MAPK signaling in vitro, which could be targeted by MEK inhibitors. Comparison of the incidence of BRAF alterations in IDC-P between western and Chinese ancestry revealed an increased prevalence in the Chinese population. The BRAF mutation may represent important genetic alteration in a subset of IDC-P, highlighting the role of MAPK signaling pathway in this subtype of PCa. To the best of knowledge, this is the first description of non-V600 BRAF mutation in setting of IDC-P, which may in part explain the aggressive phenotype seen in IDC-P and could also bring more treatment options for PCa patients with IDC-P harboring such mutations.

A spine segmentation method based on scene aware fusion network.

BACKGROUND: Intervertebral disc herniation, degenerative lumbar spinal stenosis, and other lumbar spine diseases can occur across most age groups. MRI examination is the most commonly used detection method for lumbar spine lesions with its good soft tissue image resolution. However, the diagnosis accuracy is highly dependent on the experience of the diagnostician, leading to subjective errors caused by diagnosticians or differences in diagnostic criteria for multi-center studies in different hospitals, and inefficient diagnosis. These factors necessitate the standardized interpretation and automated classification of lumbar spine MRI to achieve objective consistency. In this research, a deep learning network based on SAFNet is proposed to solve the above challenges. METHODS: In this research, low-level features, mid-level features, and high-level features of spine MRI are extracted. ASPP is used to process the high-level features. The multi-scale feature fusion method is used to increase the scene perception ability of the low-level features and mid-level features. The high-level features are further processed using global adaptive pooling and Sigmoid function to obtain new high-level features. The processed high-level features are then point-multiplied with the mid-level features and low-level features to obtain new high-level features. The new high-level features, low-level features, and mid-level features are all sampled to the same size and concatenated in the channel dimension to output the final result. RESULTS: The DSC of SAFNet for segmenting 17 vertebral structures among 5 folds are 79.46 ± 4.63%, 78.82 ± 7.97%, 81.32 ± 3.45%, 80.56 ± 5.47%, and 80.83 ± 3.48%, with an average DSC of 80.32 ± 5.00%. The average DSC was 80.32 ± 5.00%. Compared to existing methods, our SAFNet provides better segmentation results and has important implications for the diagnosis of spinal and lumbar diseases. CONCLUSIONS: This research proposes SAFNet, a highly accurate and robust spine segmentation deep learning network capable of providing effective anatomical segmentation for diagnostic purposes. The results demonstrate the effectiveness of the proposed method and its potential for improving radiological diagnosis accuracy.

A novel mouse model of central cord syndrome.

Patients with potential spinal stenosis are susceptible to central cord syndrome induced by blunt trauma. Suitable animal models are helpful for studying the pathogenesis and treatment of such injuries. In this study, we established a mouse model of acute blunt traumatic spinal cord injury by compressing the C6 spinal cord with 5 and 10 g/mm2 compression weights to simulate cervical central cord syndrome. Behavioral testing confirmed that this model exhibited the characteristics of central cord syndrome because motor function in the front paws was impaired, whereas basic motor and sensory functions of the lower extremities were retained. Hematoxylin-eosin staining showed that the diseased region of the spinal cord in this mouse model was restricted to the gray matter of the central cord, whereas the white matter was rarely affected. Magnetic resonance imaging showed a hypointense signal in the lesion after mild and severe injury. In addition, immunofluorescence staining showed that the degree of nerve tract injury in the spinal cord white matter was mild, and that there was a chronic inflammation reaction. These findings suggest that this mouse model of central cord syndrome can be used as a model for preclinical research, and that gray matter is most vulnerable to injury in central cord syndrome, leading to impaired motor function.

Establishing a Mouse Contusion Spinal Cord Injury Model Based on a Minimally Invasive Technique.

Using minimally invasive methods to model spinal cord injury (SCI) can minimize behavioral and histological differences between experimental animals, thereby improving the reproducibility of the experiments. These methods need two requirements to be fulfilled: clarity of the surgical anatomical pathway and simplicity and convenience of the laboratory device. Crucially for the operator, a clear anatomical pathway provides minimally invasive exposure, which avoids additional damage to the experimental animal during the surgical procedures and allows the animal to maintain a consistent and stable anatomical morphology during the experiment. In this study, the use of a novel integrated platform called the SCI coaxial platform for spinal cord injury in small animals to expose the T9 level spinal cord in a minimally invasive way and stabilize and immobilize the vertebra of mice using a vertebral stabilizer is researched, and, finally, a coaxial gravity impactor is used to contuse the spinal cord of mice to approach different degrees of T9 spinal cord injury. Finally, histological results are provided as a reference for the readers.

Physiological and transcriptome analyses reveal the response of Ammopiptanthus mongolicus to extreme seasonal temperatures in a cold plateau desert ecosystem.

Ammopiptanthus mongolicus is the only evergreen broad-leaved shrub present in arid areas of Northwest China and plays an important role in maintaining the stability of the local desert ecosystem. It can survive under extreme temperatures (e.g., extreme low temperature: - 24.8 °C and extreme high temperature: 37.7 °C). To understand the gene expression-physiological regulation network of A. mongolicus in extreme temperature environments, we monitored the changes in gene expression and photosynthetic traits of the leaves. The results showed that at low temperatures, the net photosynthetic rates (A), Fv'/Fm' and electron transport rate (ETR) decreased, the Fv/Fm ratio was only 0.32, and the proportion of nonregulatory heat dissipation Y(NO) increased. Based on a KEGG analysis of the differentially expressed genes, 15 significantly enriched KEGG pathways were identified, which were mainly related to circadian rhythm, photosynthesis, lipid metabolism, carbohydrate metabolism, plant hormones and other life activities. At high temperatures, the A value increased, and the proportion of regulatory energy dissipation Y(NPQ) increased. The KEGG analysis identified 24 significantly enriched KEGG pathways, which are mainly related to circadian rhythm, carbon sequestration of photosynthesis, carotenoid biosynthesis, secondary metabolites, cofactors and vitamin metabolism. In general, at the expense of photosynthesis, A. mongolicus can ensure the survival of leaves by increasing Y(NO) levels, regulating the circadian rhythm, increasing the synthesis of unsaturated fatty acids and changing the role of plant hormones. Under high-temperature stress, a high photosynthetic capacity was maintained by adjusting the stomatal conductance (gsw), increasing Y(NPQ), consuming excess light energy, continuously assembling and maintaining PSII, and changing the production of antioxidants.

Enhancement of Dissolving Capacity and Reducing Gastric Mucosa Irritation by Complex Formation of Resibufogenin with ß-Cyclodextrin or 2-Hydroxypropyl-ß-cyclodextrin.

Resibufogenin (RBG) is a natural medicinal ingredient with promising cardiac protection and antitumor activity. However, poor solubility and severe gastric mucosa irritation restrict its application in the pharmaceutical field. In this study, the inclusion complex of RBG with ß-cyclodextrin (ß-CD) and 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) was prepared using the co-evaporation method, and the molar ratio of RBG to CD was determined to be approximately 1:2 by continuous variation plot for both CDs. The formation of inclusion complexes between RBG and each CD (RBG/ß-CD and RBG/HP-ß-CD) was evaluated by phase solubility study, Fourier transform infrared spectroscopy, and thin-layer chromatography. Powder X-ray diffraction and differential scanning calorimetry confirmed drug amorphization and encapsulation in the molecular cage for both CDs. Moreover, the inclusion complexes' morphologies were observed using scanning electron microscopy. The dissolution rate of the inclusion complexes was markedly improved compared to that of RBG, and the complexes retained their antitumor activity, as shown in the in vitro cytotoxicity assay on a human lung adenocarcinoma cancer (A549) cell line. Moreover, less gastric mucosal irritation was observed for the inclusion complex. Thus, the inclusion complex should be considered a promising strategy for the delivery of poorly water-soluble anticancer agents, such as RBG.

Antioxidant interventions in autism spectrum disorders: A meta-analysis.

BACKGROUND: Autism spectrum disorder (ASD) might be associated with oxidative stress, and antioxidants are commonly used in the treatment of young people with ASD. However, the evidence about the effectiveness of these interventions remains debatable. We performed a meta-analysis to evaluate the effect of antioxidants on the symptoms of patients with autism. METHODS: Data sources: PubMed and Web of Science databases. STUDY SELECTION: We selected placebo-controlled, double-blind, randomized clinical trials published until February 2021 to evaluate the efficacy of antioxidant interventions on ASD. DATA ANALYSIS: Aberrant Behavior Checklist (ABC), Repetitive Behavior Scale-Revised (RBS), Social Responsiveness Scale (SRS), Developmental Behavior Checklist (DBC) and Clinical Global Impressions Severity scale (CGIS) were used to evaluate the 22 different symptom outcomes. The Hedges-adjusted g value was used to estimate the effect of each dietary intervention relative to the placebo. RESULTS: In this meta-analysis, we examined 13 double-blind randomized clinical trials, comprising a total of 570 patients with ASD: 293 in the intervention group and 277 in the placebo group. Antioxidants (N-acetylcysteine (NAC), other antioxidants) are more effective than placebos in improving the irritability among symptoms in the ABC and communication disturbance symptoms in the DBC. There was a good trend of improvement in the stereotypic behavior symptoms in the ABC. Treatment with NAC antioxidants showed a good trend of improvement in irritability in the ABC and symptoms of hyperactivity. The effect size was small, and there was a low risk of statistical heterogeneity and publication bias. LIMITATIONS: The number of studies in this meta-analysis was small and the sample size was small. CONCLUSION: This meta-analysis suggests that antioxidant intervention has a potential role in the management of some symptoms in patients with ASD, and indicates the feasibility of using antioxidants to treat autism in the future.

Application of the novel nano delivery systems in drug-induced pyroptosis of tumor cells / 中国肿瘤生物治疗杂志

@#[Abstract] With the rapid development of nano delivery systems (NDSs) and in-depth understanding of the mechanism of cell pyroptosis, a new tumor treatment strategy formed by an ingenious combination of the two has achieved certain effects in the experimental treatment of some tumors. The strategy of inducing pyroptosis of tumor cells based on NDSs can overcome the defects of using small molecule pyroptosis inducers alone, such as fast elimination in vivo, systemic serious adverse reactions and weak tumor-targeting ability. A variety of NDSs, such as liposomes, hydrogels, polymer micelles, metal-organic frameworks (MOFs) and cell membrane biomimetic nanocarriers, have been used to construct drugs that induce tumor cell pyroptosis. On this basis, a variety of strategies based on NDSs drug-induced tumor cell have been developed, including targeting tumor stem cells, interfering with ion homeostasis, promoting ROS production, inducing epigenetic changes and delivery of gasdermin (GSDM) family proteins, etc. However, to apply these strategies clinically we still faced insufficient understanding of the interaction mechanisms between nanomaterials and biological systems. In future researches, based on a comprehensive understanding of the interaction between nanomaterials and biological systems, if we can develop new and safe NDSs, combined with effective pyroptosis inducers to target and induce tumor cell pyroptosis, so as to overcome apoptosis escape and multidrug resistance, it is expected to bring good news to tumor patients.

A computer-aided chem-photodynamic drugs self-delivery system for synergistically enhanced cancer therapy.

The therapeutic strategy that gives consideration to the combination of photodynamic therapy and chemotherapy, has emerged as a potential development of effective anti-cancer medicine. Nevertheless, co-delivery of photosensitizers (PSs) and chemotherapeutic drugs in traditional carriers still remains great limitations due to low drug loadings and poor biocompatibility. Herein, we have utilized a computer-aided strategy to achieve a desired carrier-free self-delivery of pyropheophorbide a (PPa, a common PS) and podophyllotoxin (PPT, a classical chemotherapeutic drug) for synergistic cancer therapy. First, the computational simulation method identified the similar molecular sizes and rigid molecular structures between two drugs molecules. Based on the molecular docking, the intermolecular interactions were found to include π-π stackings, hydrophobic interactions and hydrogen bonds. Next, both drugs could co-assemble into nanoparticles (NPs) via one-step nanoprecipitation method. The various spectral experiments (UV, IR and FL) were conducted to evaluate the formation mechanism of spherical NPs. Moreover, in vitro and in vivo experiments systematically demonstrated that PPT/PPa NPs not only showed better cellular uptake efficiency, stronger cytotoxicity and higher accumulation in tumor sites, but also exhibited synergistic antitumor effect in female BALB/C bearing-4T1 tumor mice. Such a computer-aided design strategy of chem-photodynamic drugs self-delivery systems pave the way for efficient synergistic cancer therapy.

Exosome Transplantation From Patients With Schizophrenia Causes Schizophrenia-Relevant Behaviors in Mice: An Integrative Multi-omics Data Analysis.

Exosomes are involved in the pathophysiology of neuropsychiatric diseases, but the role of exosomes in schizophrenia (SCZ) is unclear. Here, we demonstrate that transplantation of serum exosomes from SCZ patients into mice caused behavioral abnormalities such as deficits in prepulse inhibition and sociability, hyperactivity, and anxiogenesis. A comparative bioinformatics analysis suggested shared and distinct differentially expressed genes (DEGs) and enriched molecular pathways in the brains of SCZ exosome-recipient mice, methylazoxymethanol acetate-treated rats, and SCZ patients, which correlates evidence of altered prefrontal-hippocampal functional coherence in SCZ. A large proportion of SCZ-relevant DEGs in the exosome-recipient mice were targets of DE exosomal miRNAs in SCZ patients. Furthermore, we identified 20 hub genes for SCZ risk genes, including BDNF and NRG1, which were DE miRNA targets in SCZ. Collectively, our study suggests that SCZ exosome transplantation caused SCZ-relevant behaviors in mice, and epigenetic regulation may contribute to the phenotypes in the SCZ exosome-recipient mice. Our results may provide a potential animal model and novel therapeutic targets for SCZ.

Ratiometric Delivery of Mitoxantrone and Berberine Co-encapsulated Liposomes to Improve Antitumor Efficiency and Decrease Cardiac Toxicity.

Combination therapy is one of the most common clinical practices in the treatment of malignancies. Synergistic effects, however, are produced only when optimal ratios of combined drugs were delivered to tumor cells. Thus, carriers co-encapsulating of multiple drugs are widely utilized for coordinated delivery. Herein, co-encapsulated pegylated liposomal formulation of mitoxantrone (MIT) and berberine (BER) at an optimal ratio has been developed (MBL) with high encapsulation efficiency (EE) and drug loading in order to achieve the purpose of ratiometric loading and delivery. MBL can not only extend blood circulation but also enhance tumor accumulation for both MIT and BER. More importantly, MBL can maintain the originally desired drug ratio in tumors within 48 h of intravenous injection for synergistic therapy. Compared with the liposomal formulation of MIT-treated group (ML), the progression of tumor growth was inhibited significantly in murine 4T1 breast tumor model after the treatment of MBL, as well as a lower cardiac toxicity. In addition, MBL evidently prolonged the survival of mice with L1210 ascitic tumor model. In summary, such a strategy of co-encapsulated liposomes could improve the clinical applications against multiple cancers.

Improved antitumor activity and tolerability of cabazitaxel derived remote-loading liposomes.

The value of the clinical application of chemotherapeutic drugs is dependent on both systemic toxicity and treatment efficacy. Dose intensification and high tolerability suggest the potential for clinical cancer therapy. In this study, we developed a novel strategy for reconstructing a drug molecule into remote-loading liposomes. Two weak-base cabazitaxel derivatives were synthesized, and named CN and CN2. CN exhibited higher cytotoxic effects compared to CN2, and was selected for further study. CN was remotely loaded into nano-size liposomes (CN-LPs) via an ammonium sulfate gradient with high loading and encapsulation efficiency. When compared to the commercial formulation of cabazitaxel, JEVTANA®, CN-LPs showed less systemic toxicity and enhanced tolerability, with at least a 24-fold increase in the tolerated dose. Furthermore, CN-LPs significantly inhibited tumor growth in mice bearing 4T1 and RM-1 xenograft tumors. After intravenous injection, CN-LPs exhibited an extremely high drug concentration in blood, with a 757-fold increase in the area under the curve (AUC). Moreover, 48 h after a single intravenous injection, CN-LPs promoted higher drug accumulation in tumors compared to JEVTANA®. In summary, our liposome delivery system exhibits favorable pharmacologic efficacy and an improved safety profile.

Cytochrome P450 enzyme-mediated auto-enhanced photodynamic cancer therapy of co-nanoassembly between clopidogrel and photosensitizer.

Reactive oxygen species (ROS)-based photodynamic therapy (PDT) has a widespread application in cancer therapy. Nevertheless, the efficiency of PDT is far from satisfactory. One major impediment is the overexpression of glutathione (GSH) in tumor cells, which could deplete the level of PDT-generated ROS. Herein, we develop a novel type of cytochrome P450 enzyme-mediated auto-enhanced photodynamic co-nanoassembly between clopidogrel (CPG) and photosensitizer pyropheophorbide a (PPa). Methods: In this work, we prepare the co-assembled nanoparticles of CPG and PPa (CPG/PPa NPs) by using one-step precipitation method. The assembly mechanism, drug release behavior, GSH consumption, ROS generation, cellular uptake, cytotoxicity of CPG/PPa NPs are investigated in vitro. The mice bearing 4T1 tumor are employed to evaluate in vivo biodistribution and anti-tumor effect of CPG/PPa NPs. Results: Such CPG/PPa NPs could disrupt the intracellular redox homeostasis, resulting from the elimination of GSH by CPG active metabolite mediated by cytochrome P450 enzyme (CYP2C19). The in vivo assays reveal that CPG/PPa NPs not only increase the drug accumulation in tumor sites but also significantly suppress tumor growth in BALB/c mice bearing 4T1 tumor. With CPG-mediated GSH consumption and PPa-triggered ROS generation, CPG/PPa NPs show the enhanced PDT treatment effect by breaking intracellular redox balance. Conclusion: Our findings provide a valuable knowledge for the rational design of the PDT-based combinational cancer therapy.

Impacts of particle shapes on the oral delivery of drug nanocrystals: Mucus permeation, transepithelial transport and bioavailability.

For drug nanocrystals (NCs), particle shapes can affect aqueous solubility, dissolution rate and oral bioavailability. However, the effects of particle shapes on the transport of NCs across the intestinal barriers remain unclear. In the present study, spherical, rod-shaped and flaky NCs (SNCs, RNCs, and FNCs) were prepared and characterized. Meanwhile, fluorescence resonance energy transfer molecules were used to track the fate of intact NCs. Results showed that particle shapes had great influences on the mucus permeation, cellular uptake and transmembrane transport of NCs, and RNCs exhibited the best absorption efficiency. Besides, we found that endoplasmic reticulum/Golgi and Golgi/plasma membrane pathways might be involved in the transcytosis and exocytosis of NCs. Moreover, the oral bioavailability study showed that AUC0-24h of RNCs was 1.44-fold and 1.8-fold higher than that of SNCs and FNCs, respectively. Collectively, these results provided compelling evidences that RNCs could potentially improve the absoption efficacy of NCs in oral delivery. Our findings give deep insights into the impacts of particle shapes on the oral absoption of NCs and provide valuable knowledge for rational design of optimized NCs for oral drug delivery.

Development of a method to quantify total and free irinotecan and 7-ethyl-10-hydroxycamptothecin (SN-38) for pharmacokinetic and bio-distribution studies after administration of irinotecan liposomal formulation.

In 2015, liposomal formulation of irinotecan (ONIVYDE) has been approved by FDA and widely applied in the treatment of pancreatic cancer. ONIVYDE is a novel liposome formulation, entrapping CPT-11 in the aqueous core of vesicles using a modified gradient loading method. Due to toxicity concerns, it is essential to explore a rapid and reliable method to effectively isolate and quantify the non-liposomal, namely, free CPT-11and total CPT-11 in plasma. This study focuses on separation of non-liposomal CPT-11, evaluation of the pharmacokinetics of free CPT-11 and total CPT-11 and bio-distribution after intravenous administration of CPT-11 liposome. Free CPT-11 in plasma was separated by solid-phase extraction (SPE). The amount of total CPT-11 and main metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) in plasma was quantified by ultra-performance liquid chromatography-MS/MS. The calibration curves fitted well and lower limit of quantitation for SN-38, free CPT-11, total CPT-11 and CPT-11 in tissue and were 5 ng/ml, 10 ng/ml, 4.44 ng/ml and 25 ng/ml respectively. The recoveries, precision and accuracy of the method appear satisfactory. Using this method, the pharmacokinetics and bio-distribution of CPT-11 liposome formulation after an intravenous dose of 2.5 mg/kg were then investigated.

The influence of trapping agents on the antitumor efficacy of irinotecan liposomes: head-to-head comparison of ammonium sulfate, sulfobutylether-ß-cyclodextrin and sucrose octasulfate.

Remote loading technology is an outstanding achievement in liposome-based drug delivery systems. Compared with conventional passive loading, remote loading technology exhibits unique superiority in terms of high drug loading efficiency, low leakage rate and adequate drug accumulation. In the intra-liposome aqueous phase, the counterion of the trapping agent can control the state of aggregation/crystallization of the drug-counterion salt, and thereby contribute to control the efficiency of remote loading. Herein, irinotecan (CPT-11)-loaded liposomes were developed using three trapping agents: ammonium sulfate (AS), sulfobutylether-ß-cyclodextrin (SBE-ß-CD) and sucrose octasulfate (SOS). The corresponding formulations were named as AS liposomal CPT-11, TEA-SBE-ß-CD liposomal CPT-11 and TEA-SOS liposomal CPT-11, respectively. Cryo-transmission electron micrographs showed that bundles of CPT-11 fibers were gathered inside TEA-SOS liposomal CPT-11. Furthermore, compared with AS liposomal CPT-11 and TEA-SBE-ß-CD liposomal CPT-11, TEA-SOS liposomal CPT-11 demonstrated slower drug release, prolonged circulation time and significantly improved antitumor efficiency. To avoid the protection of ONIVYDE®-related patents, a number of other liposomal CPT-11 formulations are under preclinical investigation or even in clinical trials. Our study gives new insights into the impact of the trapping agent on remote loading, and provides valuable information to evaluate the development of CPT-11 loaded liposomes.

Repurposing antitubercular agent isoniazid for treatment of prostate cancer.

The development of versatile antitumor agents with tumor-imaging, targeting and therapeutic activity is promising for clinical cancer therapy. Prostate cancer is still the one of the leading threats to males. Current therapies have restricted clinical efficiency for patients with advanced and metastatic prostate cancer. Recent studies demonstrate that monoamine oxidase A (MAOA) levels elevate with prostate cancer aggression and metastasis. In addition, MAOA inhibitor therapies have been reported as an effective means to reduce the metastasis of prostate cancer and extend mouse survival. Thus, these findings provide evidence that MAOA is promising for the treatment of metastatic and advanced prostate cancer. Herein, three isoniazid (INH)-dye conjugates were synthesized by conjugating MAOA inhibitor INH with mitochondria-targeting NIRF heptamethine dyes to improve the therapeutic efficacy of prostate cancer. These INH-dye conjugates could accumulate in PC-3 cellular mitochondria via organic anion transport peptide (OATP), increase ROS generation, and induce cancer cells apoptosis. In prostate cancer bearing xenografts, INH-dye conjugates showed significantly improved tumor-homing characteristics, resulting in potent antitumor activity via a reduction in MAOA activity. These results suggest that INH-dye conjugates have great potential to be used as versatile antitumor agents with prostate cancer targeting, NIR imaging, and potent antitumor efficacy.

Prostate-Specific Membrane Antigen Targeted Therapy of Prostate Cancer Using a DUPA-Paclitaxel Conjugate.

Prostate cancer (PCa) is the most prevalent cancer among men in the United States and remains the second-leading cause of cancer mortality in men. Paclitaxel (PTX) is the first line chemotherapy for PCa treatment, but its therapeutic efficacy is greatly restricted by the nonspecific distribution in vivo. Prostate-specific membrane antigen (PSMA) is overexpressed on the surface of most PCa cells, and its expression level increases with cancer aggressiveness, while being present at low levels in normal cells. The high expression level of PSMA in PCa cells offers an opportunity for target delivery of nonspecific cytotoxic drugs to PCa cells, thus improving therapeutic efficacy and reducing toxicity. PSMA has high affinity for DUPA, a glutamate urea ligand. Herein, a novel DUPA-PTX conjugate is developed using DUPA as the targeting ligand to deliver PTX specifically for treatment of PSMA expressing PCa. The targeting ligand DUPA enhances the transport capability and selectivity of PTX to tumor cells via PSMA mediated endocytosis. Besides, DUPA is conjugated with PTX via a disulfide bond, which facilitates the rapid and differential drug release in tumor cells. The DUPA-PTX conjugate exhibits potent cytotoxicity in PSMA expressing cell lines and induces a complete cessation of tumor growth with no obvious toxicity. Our findings give new insight into the PSMA-targeted delivery of chemotherapeutics and provide an opportunity for the development of novel active targeting drug delivery systems for PCa therapy.