Dual-Targeting Macrophages and Hepatic Stellate Cells by Modified Albumin Nanoparticles for Liver Cirrhosis Treatment.

Hepatic cirrhosis has become a global public health concern with high mortality and currently lacks effective clinical treatment methods. Activation of hepatic stellate cells (HSCs) and the large number of macrophages infiltrating into the liver play a critical role in the development of liver cirrhosis. This study developed a novel modified nanoparticle system (SRF-CS-PSA NPs) in which Sorafenib (SRF) was encapsulated by palmitic acid-modified albumin (PSA) and further modified with chondroitin sulfate (CS). These modifications enabled the SRF-CS-PSA NPs to effectively target hepatic stellate cells (HSCs) and macrophages. SRF-CS-PSA NPs showed uniform particle size distribution of approximately 120 nm and high loading efficiency of up to 99.5% and can be taken up by HSCs and macrophages via CD44 and SR-A receptors, respectively. In a mouse model of liver cirrhosis, SRF-CS-PSA NPs demonstrated superior targeting and inhibition of HSCs and macrophages, effectively reversing the process of liver cirrhosis. Overall, our study demonstrates the potential of SRF-CS-PSA NPs as a targeted therapy for liver cirrhosis, with promising clinical applications.

Combined Amphiphilic Silybin Meglumine Nanosuspension Effective Against Hepatic Fibrosis in Mice Model.

Introduction: Silybin (SLB) as an effective hepatoprotective phytomedicine has been limited by its hydrophobicity, poor bioavailability and accumulation at lesion sites. Additionally, present drug loading methods are impeded by their low drug loading capacity, potential hazard of materials and poor therapeutic effects. Consequently, there is a pressing need to devise an innovative approach for preparing nanosuspensions loaded with both SLB and Silybin Meglumine salt (SLB-M), as well as to investigate the therapeutic effects of SLB nanosuspensions against hepatic fibrosis. Methods: The SLB nanosuspension (NS-SLB) was prepared and further modified with a hyaluronic acid-cholesterol conjugate (NS-SLB-HC) to improve the CD44 targeting proficiency of NS-SLB. To validate the accumulation of CD44 and ensure minimal cytotoxicity, cellular uptake and cytotoxicity assessments were carried out for the nanosuspensions. Western blotting was employed to evaluate the anti-hepatic fibrosis efficacy in LX-2 cells by inhibiting the secretion of collagen I. Hepatic fibrosis mouse models were used to further confirm the effectiveness of NS-SLB and NS-SLB-HC against hepatic fibrosis in vivo. Results: Uniform nanosuspensions were prepared through self-assembly, achieving high drug loading rates of 89.44% and 60.67%, respectively. Both SLB nanosuspensions showed minimal cytotoxicity in cellular environments and mitigated hepatic fibrosis in vitro. NS-SLB-HC was demonstrated to target activated hepatic stellate cells by receptor-ligand interaction between HA and CD44. They can reverse hepatic fibrosis in vivo by downregulating TGF-ß and inhibiting the secretion of α-SMA and collagen I. Conclusion: Designed as a medical excipient analogue, SLB-M was aimed to establish an innovative nanosuspension preparation method, characterized by high drug loading capacity and a notable impact against hepatic fibrosis.

Palmitic acid-modified human serum albumin paclitaxel nanoparticles targeting tumor and macrophages against breast cancer.

Breast cancer is the most common malignant tumor in women, and the liver is the main target organ for breast cancer metastasis. Once metastasis occurs, the prognosis is very poor. The uptake of PSA NPs made by our synthesized Palmitic acid-modified human serum albumin (PSA) in macrophages is about 15 times higher than that of HSA NPs. As a first-line chemotherapeutic drug, paclitaxel not only does not kill macrophages, but it can also polarize macrophages into classically activated macrophages (M1). We combined these two characteristics into PTX-PSA NPs, which achieved dual targeting of macrophages and tumor cells, improved the tumor microenvironment, and achieved a more effective anti-breast cancer drug effect than PTX-HSA NPs. On this basis, we also used the pathological characteristics of low vascular perfusion of breast cancer liver metastasis, and used the characteristics of macrophages that can release paclitaxel after internalizing paclitaxel, and use macrophages as the delivery system of breast cancer liver metastasis. Therefore,PTX-PSA NPs is better than PTX-HSA NPs to achieve anti-breast cancer liver metastasis.

Chondroitin sulfate-based prodrug nanoparticles enhance photodynamic immunotherapy via Golgi apparatus targeting.

Photodynamic therapy (PDT) is an emerging therapeutic approach that can inhibit tumor growth by destroying local tumors and activating systemic antitumor immune responses. However, PDT can be ineffective because of photosensitizer aggregation, tumor-induced dendritic cells (DCS) dysfunction and PDT-mediated immunosuppression. Therefore, we designed chondroitin sulfate-based prodrug nanoparticles for the co-delivery of the photosensitizer chlorin e6 (Ce6) and retinoic acid (RA), which can reduce PDT-mediated immunosuppression by disrupting the Golgi apparatus and blocking the production of immunosuppressive cytokines. Moreover, CpG oligodeoxynucleotide was combined as immunoadjuvant to promote the maturation of DCs. As expected, the strategy of Golgi apparatus targeting immunotherapy combined PDT was confirmed to relieve PDT-induced immunosuppression, showed excellent PDT antitumor efficacy in B16F10-subcutaneous bearing mice model. Thus, our finding offers a promising approach for photodynamic immunotherapy of advanced cancers. STATEMENT OF SIGNIFICANCE: Golgi apparatus has been shown to be a potential target of immunosuppression for producing several immunosuppressive cytokines. In this work, a Golgi apparatus-targeted prodrug nanoparticle was developed to enhance the immune response in photodynamic immunotherapy. The nanoparticle can target and disrupt the Golgi apparatus in tumor cells, which reduced PDT-mediated immunosuppression by blocking the production of immunosuppressive cytokines. This work provides an effective strategy of PDT in combination with the Golgi apparatus-targeted nanovesicle for enhanced cancer therapy.

Dual-Targeting of Tumor Cells and Tumor-Associated Macrophages by Palmitic Acid Modified Albumin Nanoparticles for Antitumor and Antimetastasis Therapy.

Tumor-associated macrophages (TAMs), the most abundant immune cells in the tumor microenvironment (TME), profoundly affect the occurrence and development of tumors. To overcome the common limitations of TAMs-targeted delivery systems, such as off-target toxicity, high cost, and transformation probability, we fabricated pirarubicin (THP)-loaded palmitic acid modified human serum albumin nanoparticles (THP-PSA NPs) for dual-targeting of tumor cells and TAMs via acidic secretory proteins rich in cysteine (SPARC) and scavenger receptor-A (SR-A), respectively. In vitro, the THP-PSA NPs exhibit stronger cytotoxicity against 4T1 and M2 macrophages compared with THP-loaded human serum albumin nanoparticles (THP-HSA NPs). In vivo, the infiltration of myeloid-derived suppressor cells (MDSCs) and the secretion of immunosuppressive cytokines significantly decrease after effective elimination of the TAMs through the THP-PSA NPs treatment; this is accompanied by an increase in the immunostimulatory cytokine expression level. Moreover, the antitumor and antimetastasis experimental results indicate that the tumor volumes in mice treated with the THP-PSA NPs are effectively controlled, resulting in an inhibition rate of 81.0% and almost no metastases in the lung tissues. Finally, in terms of biological safety, the THP-PSA NPs perform similar to THP-HSA NPs, causing no damage to the liver or kidney.

Targeted delivery of celastrol to glomerular endothelium and podocytes for chronic kidney disease treatment.

The etiology of chronic kidney disease (CKD) is complex and diverse, which could be briefly categorized to glomerular- or tubular-originated. However, the final outcomes of CKD are mainly glomerular sclerosis, endothelial dysfunction and injury, and chronic inflammation. Thus, targeted delivery of drugs to the glomeruli in order to ameliorate glomerular endothelial damage may help alleviate CKD and help enrich our knowledge. The herb tripterygium wilfordii shows therapeutic effect on kidney disease, and celastrol (CLT) is one of its active ingredients but with strong toxicity. Therefore, based on the unique structure and pathological characteristics of the glomerulus, we designed a targeted delivery system named peptides coupled CLT-phospholipid lipid nanoparticles (PC-PLNs) to efficiently deliver CLT to damaged endothelial cells and podocytes in the glomerulus for CKD treatment and research. PC-PLNs could effectively inhibit inflammation, reduce endothelial damage, alleviate CKD severity, and reduce the toxicity of CLT. We also studied the mechanism of CLT in the treatment of nephropathy and found that CLT can increase the level of NO by increasing eNOS while inhibiting the expression of VCAM-1, thus provides an anti-inflammatory effect. Therefore, our study not only offered an efficient CKD drug formulation for further development, but also provided new medical knowledge about CKD. Electronic Supplementary Material: Supplementary material (attached with all the supporting tables and figures mentioned in this work) is available in the online version of this article at 10.1007/s12274-021-3894-x.

Alternative and Injectable Preformed Albumin-Bound Anticancer Drug Delivery System for Anticancer and Antimetastasis Treatment.

Biomimetic design has been extensively investigated. The only FDA-approved biomimetic albumin-bound paclitaxel may not be beneficial to some treated patients due to rapid dissociation upon intravenous infusion and no substantial improvement in the drug's pharmacokinetics or biodistribution. Herein, we developed an alternative and injectable preformed albumin-bound anticancer drug delivery. We combined HSA, Kolliphor HS 15 (HS15), and pirarubicin (THP) via purely physical forces in a thin-film hydration method to obtain an albumin-bound complex of HSA-THP. The lack of any chemical reactions preserves HSA bioactivity, in contrast to the destroyed secondary structure within AN-THP (albumin nanoparticle of THP) for the harsh manipulation during preparation. In vitro, HSA-THP showed a significantly higher cellular uptake efficiency than THP, and the complex was more cytotoxic. In vivo, HSA-THP showed longer half-life than THP. It also exhibited greater tumor accumulation and tumor penetration via gp60- and SPARC-mediated biomimetic transport than THP and AN-THP. As a result, HSA-THP showed strong antitumor and antimetastasis efficacy, with relatively little toxicity. These results suggest the clinical potential of biomimetic tumor-targeted drug delivery.

High-water-absorbing calcium alginate fibrous scaffold fabricated by microfluidic spinning for use in chronic wound dressings.

More and more water-absorbing wound dressings have been studied since moist wound-healing treatment can effectively promote the healing of wounds. In this work, we introduce a novel method to produce improved wound dressings with high-water-absorbance. A high-water-absorbing calcium alginate (Ca-Alg) fibrous scaffold was fabricated simply by microfluidic spinning and centrifugal reprocessing. The structure and physical properties of the scaffold were characterized, and its water-absorbing, cytotoxicity properties and other applicability to wound dressings were comprehensively evaluated. Our results indicate that this material possesses high water-absorbing properties, is biocompatible, and has a 3D structure that mimics the extracellular matrix, while Ca-Alg fibers loaded with silver nanoparticles (AgNPs) exhibit broad-spectrum antibacterial activities; these properties meet the requirements for promoting the healing of chronic wounds and are widely applicable to wound dressings.