Occurrence and influencing factors of cyclosporine A on the kidney injury following allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis.

OBJECTIVE: Whether cyclosporine A (CsA) is a risk factor of kidney injury after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has not been determined. We aim to comprehensively review the correlation and influencing factors between CsA and kidney injury in patients following allo-HSCT. METHODS: We searched PubMed, Embase (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), CNKI, VIP, Wanfang and CBM Database from inception to March 2022. Two researchers independently conducted literature screening, data extraction and quality assessment. Qualitative and quantitative methods were combined to analyze the data. RESULTS: We included a total of 30 studies. Meta-analyses of total incidence of kidney injury related to CsA was 37.0% [95% CI (25.4%, 48.6%); n = 15]. The proportion of CsA-related acute kidney injury to total acute kidney injury following allo-HSCT was 59.7% [95% CI (49.1%, 70.3%); n = 9]. One study found that AKI had a significant association with CsA in multivariate analysis [RR = 6.173; 95% CI (4.032, 9.434)]. With respect to cyclosporine combination and nephrotoxicity, 6/9 studies demonstrated that the concomitant medications for CsA (especially aminoglycoside antibiotics and amphotericin B) had negative effect on kidney functions related to CsA in allo-HSCT patients. No consensus was reached for "dose of CsA", "duration of CsA use", "comorbidities" and "CsA levels" across studies. CONCLUSIONS: CsA may be a risk factor for kidney injury in patients following allo-HSCT, especially the concomitant use of CsA and nephrotoxic medications.

Accurate programmed multifunctional nano-missiles for self-promoted deep delivery and synergistic cascade tumor therapy: Tactfully collaborating chemosynthesis with tumor microenvironment remodeling.

Rationale: Triple-negative breast cancer (TNBC) is considered one of the highest-risk subtypes of breast cancer and has dismal prognosis. The management of aggressive TNBC remains a formidable challenge. Tumor microenvironment (TME), with the unique features, which can serve as the "soil" for the growth and survival of tumor cells (the "seeds"), plays an important regulatory role in the occurrence, proliferation and metastasis of tumors. Catalytic tumor therapy, which can destroy the homeostasis of TME, affect the occurrence and progress of tumors in an all-round way and further magnify chemotherapy, is a quite potential tactic for TNBC-treatment. Methods: Herein, accurate programmed multifunctional cascade nano-missiles (GOx+L-Arg-NM/PTX-NM) composed of novel intelligent all-in-one "nano-rocket" (the drug delivery system) and "ammunitions" (the therapeutic agents) are innovatively constructed by mimicking the functionalities of military precision-guided missiles. Ammunitions can be precisely and effectively transported to the core region of TNBC (the "battlefield") by organic modification on the surface of nano-rocket via chemical means. Once successfully internalized by TNBC cells, the nano-missiles can automatically trigger relevant cascade reactions without external stimulation, prominently disrupt the homeostasis of TME, and produce a "bomb-like" attack on tumors, further promoting the chemotherapy. Results: Both in vitro and in vivo investigations indicated that the innovative nano-missiles could deliver ammunitions to the core area of TNBC to the utmost extent, dramatically ablate tumor and restrain tumor metastasis via orchestrated multimodal synergistic starvation/oxidation/gas/chemotherapy. Conclusion: The well-designed multifunctional nano-missiles may emerge as a new paradigm to suppress the malignant proliferation and metastasis of TNBC, offering a promising approach for the next generation cancer therapy.

Berberine and folic acid co-modified pH-sensitive cascade-targeted PTX-liposomes coated with Tween 80 for treating glioma.

Chemotherapy is a conventional treatment for glioma, but its efficacy is greatly limited due to low blood-brain barrier (BBB) permeability and lack of specificity. Herein, intelligent and tumor microenvironment (TME)-responsive folic acid (FA) derivatives and mitochondria-targeting berberine (BBR) derivatives co-modified liposome coated with Tween 80 loading paclitaxel (PTX-Tween 80-BBR + FA-Lip) was constructed. Specifically speaking, liposomes modified by FA can be effectively target ed to glioma cells. BBR, due to its delocalized positive electricity and lipophilicity, can be attracted by mitochondrial membrane potential and concentrate on mitochondria to achieve mitochondrial targeting and induce cell apoptosis. By simultaneously modifying the liposome with FA and BBR to deliver drugs, leads to a good therapeutic effect of glioma through FA-based glioma targeting and BBR-based mitochondrial targeting. In addition, the surface of the liposome was coated with Tween 80 to further improve BBB penetration. All results exhibited that PTX-Tween 80-BBR + FA-Lip can observably improve the chemotherapy therapeutic efficacy through the highly specific tumor targeting and mitochondrial targeting, which can provide new ideas and methods for the targeted therapy of glioma.

Investigation of functionalised nanoplatforms using branched-ligands with different chain lengths for glioblastoma targeting.

Glioblastoma, a common malignancy of the central nervous system, is the most destructive type of brain cancer. Clinical treatment remains a major challenge due to high infiltrative growth and the presence of the blood brain barrier (BBB). Therefore, advanced nanoplatforms that can efficiently cross the BBB and target brain tumours are highly desired. Compared with the targeting efficiency of single ligand nanoplatforms, dual targeting nanoplatforms may lead to better and controllable malignant cell selectivity. In this study, based on our previous research of branched ligands, we finally determined to use tri-branched glucose and two-branched biotin as targeting molecules, and in order to explore the synergetic-targeting capabilities and the mutual influence between the length of the two ligands, we designed three kinds of two-branched biotin ligands with a different linker and co-modified with the tri-branched glucose ligands on the surface of liposomes. The results of in vivo and in vitro experiments showed the (Glu3+Bio2)-2-Lip can exert the greatest synergistic targeting ability. The application of branched ligands, the dual-targeting design concept, and the exploration of the interaction between the chain lengths of the two ligands have brought new ideas and new methods for the targeted therapy of glioma.

Skillfully collaborating chemosynthesis with GOx-enabled tumor survival microenvironment deteriorating strategy for amplified chemotherapy and enhanced tumor ablation.

The satisfactory efficient tumor treatment and complete tumor ablation using a mono-therapeutic approach are limited owing to the tumor complexity, diversity, heterogeneity and the multiple pathways involved in tumor pathogenesis. Herein, novel, intelligent and tumor microenvironment (TME)-responsive biotin/R8 peptide co-modified nanocarriers (BRNC) loading paclitaxel (PTX)/glucose oxidase (GOx) were constructed. GOx could catalyze the oxidation of intracellular glucose to gluconic acid and poisonous H2O2 to cause the deterioration of the tumor survival microenvironment, simultaneously achieving starvation and oxidation therapy. The acidic amplification during the GOx-mediated oxidation progress could in turn accelerate the cleavage of the acid-degradable hydrazone bond, promoting the deep penetration of nanocarriers into tumors. Even better, the aforementioned two aspects further increased the tumors' sensitivity to chemotherapeutic agents. Both in vitro and in vivo investigations indicated that the co-administration of GOx-BRNC and PTX-BRNC can remarkably improve the therapeutic efficacy and reduce side effects through the high-specific tumor targeting multimodal synergistic starvation/oxidation/chemotherapy, which would be a promising strategy for the next generation cancer therapy.

Biotin and glucose co-modified multi-targeting liposomes for efficient delivery of chemotherapeutics for the treatment of glioma.

Glioma is one of the most common primary intracranial tumor, but the current treatments of glioma are far from satisfying. As the major treatment option for malignant glioma, chemotherapy has its own disadvantages, including low chemotherapeutic agents delivery across blood-brain barrier (BBB) and lack of specificity. Therefore, new approach permitting glioma targeting ability that can allow an efficient therapeutic delivery into the glioma regions is urgently required. Ligand-mediated liposomes have shown great potential for improving the efficiency of glioma treatment. In our study, the multi-targeting liposomes based on glucose and biotin were constructed for the first time. We synthesized two ligands (Glu3-Chol, Bio2-Chol), prepared three types of modified liposomes (Glu3-Lip, Bio2-Lip and Bio2 + Glu3-Lip) and evaluated the glioma-targeting ability of these liposomes which were using paclitaxel (PTX) as the model drug in vitro. Besides, the uptake mechanism of Bio2 + Glu3-Lip was investigated. PTX-loaded Bio2 + Glu3-Lip (PTX-Bio2 + Glu3-Lip) exhibited satisfactory targeting effect in Bend.3 and C6 cells in vitro, in which the cellular uptake of Bio2 + Glu3-Lip were 4.04- and 3.49-fold more than that of the uncoated liposomes (Lip). The results suggested the multi-targeting liposomes (Bio2 + Glu3-Lip) is a promising formulation for glioma, which was almost consistent with the results of in vivo imaging. In summary, we have designed and fabricated an effective delivery system to treat glioma.

Liposomes modified with double-branched biotin: A novel and effective way to promote breast cancer targeting.

Although active targeting liposomes with cancer-specific ligands can bind and internalize into cancer cells, only a few high-efficiency liposomes have been developed so far because traditional single branched ligand modified liposomes generally failed to deliver adequate therapeutic payload. In this paper, we broke the traditional design concept and synthesized the double branched biotin modified cholesterol (Bio2-Chol) for the first time. On this basis, different biotin density modified liposomes ((Bio-Chol)Lip, (Bio-Chol)2Lip and (Bio2-Chol)Lip) were successfully prepared and used as active targeting drug delivery systems for the treatment of breast cancer. The in vitro and in vivo breast cancer-targeting ability of these liposomes were systemically studied using paclitaxel (PTX) as the model drug. And the uptake mechanism of (Bio2-Chol)Lip was investigated. The results showed that (Bio2-Chol)Lip had the best breast cancer-targeting ability compared with naked paclitaxel, unmodified Lip, (Bio-Chol)Lip and (Bio-Chol)2Lip. In particular, the relative uptake efficiency (RE) and concentration efficiency (CE) of (Bio2-Chol)Lip were respectively enhanced by 5.61- and 5.06-fold compared to that of naked paclitaxel. Both distribution data and pharmacokinetic parameters suggested that the double branched biotin modified liposome ((Bio2-Chol)Lip) is a very promising drug delivery carrier for breast cancer.

Design, synthesis, and neuroprotective effects of dual-brain targeting naproxen prodrug.

A new dual-targeting naproxen prodrug conjugated with glucose and ascorbic acid for central nervous system (CNS) drug delivery was designed and synthesized in order to effectively deliver naproxen to the brain. Naproxen could be released from the prepared prodrugs when incubated with various buffers, mouse plasma, and brain homogenate. Also, the prodrug showed superior neuroprotective effect in vivo over naproxen. Our results suggest that chemical modification of therapeutics with warheads of glucose and ascorbic acid represents a promising and efficient strategy for the development of brain targeting prodrugs by utilizing the endogenous transportation mechanism of the warheads.

Dual-targeting for brain-specific drug delivery: synthesis and biological evaluation.

Ibuprofen is one of the most potent non-steroid anti-inflammatory drugs (NSAIDs) and plays an important role in the treatment of neurodegenerative diseases. However, its poor brain penetration and serious side effects at therapeutic doses, has hindered its further application. Thus, it is of great interest to develop a carrier-mediated transporter (CMT) system that is capable of more efficiently delivering ibuprofen into the brain at smaller doses to treat neurodegenerative diseases. In this study, a dual-mediated ibuprofen prodrug modified by glucose (Glu) and vitamin C (Vc) for central nervous system (CNS) drug delivery was designed and synthesized in order to effectively deliver ibuprofen to brain. Ibuprofen could be released from the prepared prodrugs when incubated with various buffers, mice plasma and brain homogenate. Also, the prodrug showed superior neuroprotective effect in vitro and in vivo than ibuprofen. Our results suggest that chemical modification of therapeutics with warheads of glucose and Vc represents a promising and efficient strategy for the development of brain-targeting prodrugs by utilizing the endogenous transportation mechanism of the warheads.