Design of a targeted dual drug delivery system for boosting the efficacy of photoimmunotherapy against melanoma proliferation and metastasis.

INTRODUCTION: The combination of a photosensitizer and indoleamine-2,3 dioxygenase (IDO) inhibitor provides a promising photoimmunotherapy (PIT) strategy for melanoma treatment. A dual drug delivery system offers a potential approach for optimizing the inhibitory effects of PIT on melanoma proliferation and metastasis. OBJECTIVE: To develop a dual drug delivery system based on PIT and to study its efficacy in inhibiting melanoma proliferation and metastasis. METHODS: We constructed a multifunctional nano-porphyrin material (P18-APBA-HA) using the photosensitizer-purpurin 18 (P18), hyaluronic acid (HA), and 4-(aminomethyl) phenylboronic acid (APBA). The resulting P18-APBA-HA was inserted into a phospholipid membrane and the IDO inhibitor epacadostat (EPA) was loaded into the internal phase to prepare a dual drug delivery system (Lip\EPA\P18-APBA-HA). Moreover, we also investigated its physicochemical properties, targeting, anti-tumor immunity, and anti-tumor proliferation and metastasis effects. RESULTS: The designed system utilized the pH sensitivity of borate ester to realize an enhanced-targeting strategy to facilitate the drug distribution in tumor lesions and efficient receptor-mediated cellular endocytosis. The intracellular release of EPA from Lip\EPA\P18-APBA-HA was triggered by thermal radiation, thereby inhibiting IDO activity in the tumor microenvironment, and promoting activation of the immune response. Intravenous administration of Lip\EPA\P18-APBA-HA effectively induced anti-tumor immunity by promoting dendritic cell maturation, cytotoxic T cell activation, and regulatory T cell suppression, and regulating cytokine secretion, to inhibit the proliferation of melanoma and lung metastasis. CONCLUSION: The proposed nano-drug delivery system holds promise as offers a promising strategy to enhance the inhibitory effects of the combination of EPA and P18 on melanoma proliferation and metastasis.

Development of a hydroxypropyl methyl cellulose/polyacrylic acid interpolymer complex formulated buccal mucosa adhesive film to facilitate the delivery of insulin for diabetes treatment.

Buccal mucosa administration is a promising method for insulin (INS) delivery with good compliance. However, buccal mucosa delivery systems still face challenges of long-term mucosal adhesion, sustained drug release, and mucosal drug penetration. To address these issues, a double-layer film consisting of a hydroxypropyl methylcellulose/polyacrylic acid interpolymer complex (IPC)-formulated mucoadhesive layer and an ethylcellulose (EC)-formulated waterproof backing layer (IPC/EC film) was designed. Protamine (PTM) and INS were co-loaded in the mucoadhesive layer of the IPC/EC film (PTM-INS-IPC/EC film). In ex vivo studies with porcine buccal mucosa, this film exhibited robust adhesion, with an adhesion force of 120.2 ±â€¯20.3 N/m2 and an adhesion duration of 491 ±â€¯45 min. PTM has been shown to facilitate INS mucosal transfer. Pharmacokinetic studies indicated that the PTM-INS-IPC/EC film significantly improved the absorption of INS, exhibiting a 1.45 and 2.24-fold increase in the area under the concentration-time curve (AUC0-∞) compared to the INS-IPC/EC film and free INS, respectively. Moreover, the PTM-INS-IPC/EC film effectively stabilized the blood glucose levels of type 1 diabetes mellitus (T1DM) rats with post oral glucose administration, maintaining lower glucose levels for approximately 8 h. Hence, the PTM-INS-IPC/EC film provides a promising noninvasive INS delivery system for diabetes treatment.

Targeted treatment of atherosclerosis with protein-polysaccharide nanoemulsion co-loaded with photosensitiser and upconversion nanoparticles.

Macrophages are the most abundant cell group in atherosclerosis (AS) lesions and play a vital role in all stages of AS progression. Recent research has shown that reactive oxygen species (ROS) generation from photodynamic therapy (PDT) induces macrophage autophagy to improve abnormal lipid metabolism and inflammatory environment. Especially in macrophage-derived foam cells, which has become a potential strategy for the treatment of AS. In this study, we prepared the conjugate (DB) of dextran (DEX) and bovine serum albumin (BSA). The DB was used as the emulsifier to prepare nanoemulsion loaded with upconversion nanoparticles (UCNPs) and chlorin e6 (Ce6) (UCNPs-Ce6@DB). The DEX modified on the surface of the nanoemulsion can recognise and bind to the scavenger receptor class A (SR-A) highly expressed on macrophages and promote the uptake of macrophage-derived foam cells in AS plates through SR-A-mediated endocytosis. In addition, UCNPs-Ce6@DB-mediated PDT enhanced ROS generation and induced autophagy in macrophage-derived foam cells, enhanced the expression of ABCA1, a protein closely related to cholesterol efflux, and inhibited the secretion of pro-inflammatory cytokines. Ultimately, UCNPs-Ce6@DB was shown to inhibit plaque formation in mouse models of AS. In conclusion, UCNPs-Ce6@DB offers a promising treatment for AS.

Fabrication of a protein-dextran conjugates formed oral nanoemulsion and its application to deliver the essential oil from Alpinia zerumbet Fructus.

The injury of vascular endothelial cells caused by high glucose (HG) is one of the driving factors of vascular complications of diabetes. Oral administration is the most common route of administration for the treatment of diabetes and its vascular complications. Essential oil extracts from Chinese medicine possess potential therapeutic effects on vascular endothelial injury. However, low solubility and volatility of essential oils generally result in poor oral absorption. Development of nanocarriers for essential oils is a promising strategy to overcome the physiological barriers of oral absorption. In this study, a nanoemulsion composed of bovine serum albumin (BSA)-dextran sulfate (DS) conjugate and sodium deoxycholate (SD) was constructed. The nanoemulsions were verified with promoted oral absorption and prolonged circulation time. After the primary evaluation of the nanoemulsion, essential oil from Alpinia zerumbet Fructus (EOFAZ)-loaded nanoemulsion (denoted as EOFAZ@BD5/S) was prepared and characterized. Compared to the free EOFAZ, EOFAZ@BD5/S increased the protective effects on HG-induced HUVEC injury in vitro and ameliorative effects on the vascular endothelium disorder and tunica media fibroelastosis in a T2DM mouse model. Collectively, this study provides a nanoemulsion for the oral delivery of essential oils, which holds strong promise in the treatment of diabetes-induced vascular endothelial injury.

Fabrication of a Polysaccharide-Protein/Protein Complex Stabilized Oral Nanoemulsion to Facilitate the Therapeutic Effects of 1,8-Cineole on Atherosclerosis.

Atherosclerosis (AS) is a systemic disease characterized by lipid deposition in the blood vessel wall that urgently requires effective and safe therapeutic drugs for long-term treatment. An essential oil monomer-1,8-cineole (CIN) with ameliorative effects on vascular injuries has considerable potential for preventing the progression of AS because of its antioxidant, anti-inflammation, and cholesterol regulatory effects. However, the high volatility and instability of CIN result in low oral bioavailability and a short half-life, thereby limiting its clinical application. We formulated a nanoemulsion using a polysaccharide-protein/protein complex (dextran-bovine serum albumin/protamine, DEX5k-BSA/PTM) as an emulsifier, with vitamin B12 (VB12) as the ligand to facilitate the transportation across the small intestine. An emulsion preparation method using a microjet followed by ultraviolet irradiation was developed to obtain the CIN-loaded oral nanoemulsion CIN@DEX5k-BSA/PTM/VB12. The nanoemulsion improved the stability of CIN both in vitro and in vivo, prolonged the retention time in the gastrointestinal tract (GIT), and enhanced the permeability across the mucus layer and intestinal epithelial cells to increase oral bioavailability and plaque accumulation of CIN. Validated in an AS mouse model, CIN@DEX5k-BSA/PTM/VB12 achieved prominent therapeutic efficacy combating AS. This study highlights the advantages of DEX5k-BSA/PTM and VB12 in the development of nanoemulsions for CIN and provides a promising oral nanoplatform for the delivery of essential oils.

Carboxymethyl Chitosan Modified Oxymatrine Liposomes for the Alleviation of Emphysema in Mice via Pulmonary Administration.

Pulmonary emphysema is a fatal lung disease caused by the progressive thinning, enlargement and destruction of alveoli that is closely related to inflammation and oxidative stress. Oxymatrine (OMT), as a bioactive constituent of traditional Chinese herbal Sophora flavescens, has great potential to alleviate pulmonary emphysema via its anti-inflammatory and antioxidative activities. Pulmonary administration is the most preferable way for the treatment of lung diseases. To improve the in vivo stability and pulmonary retention of OMT, OMT-loaded liposome with carboxymethyl chitosan (CMCS) modification was developed. The CMCS was modified on the surface of OMT liposomes via electrostatic attraction and covalent conjugation to obtain Lipo/OMT@CMCS and CMCS-Lipo/OMT, respectively. A porcine pancreatic elastase (PPE)-induced emphysema mice model was established to evaluate the alleviation effects of OMT on alveolar expansion and destruction. CMCS-modified liposomal OMT exhibited superior ameliorative effects on emphysema regardless of the preparation methods, and higher sedimentation and longer retention in the lung were observed in the CMCS-Lipo group. The mechanisms of OMT on emphysema were related to the downregulation of inflammatory cytokines and the rebalancing of antioxidant/oxidation via the Nrf2/HO-1 and NF-κB/IκB-α signaling pathways, leading to reduced cell apoptosis. Moreover, the OMT liposomal preparations further enhanced its anti-inflammatory and antioxidative effects. In conclusion, pulmonary administration of OMT is a potential strategy for the treatment of emphysema and the therapeutic effects can be further improved by CMCS-modified liposomes.

Improving the ameliorative effects of berberine and curcumin combination via dextran-coated bilosomes on non-alcohol fatty liver disease in mice.

BACKGROUND: The combination of berberine (BER) and curcumin (CUR) has been verified with ameliorative effects on non-alcohol fatty liver disease (NAFLD). However, discrepant bioavailability and biodistribution of BER and CUR remained an obstacle to achieve synergistic effects. Multilayer nanovesicles have great potential for the protection and oral delivery of drug combinations. Therein lies bile salts inserted liposomes, named as bilosomes, that possesses long residence time in the gastrointestinal tract (GIT) and permeability across the small intestine. Diethylaminoethyl dextran (DEAE-DEX) is generally used as an outside layer on the nanovesicles to increase the mucinous stability and promote oral absorption. Herein, we developed a DEAE-DEX-coated bilosome with BER and CUR encapsulated (DEAE-DEX@LSDBC) for the treatment of NAFLD. RESULTS: DEAE-DEX@LSDBC with 150 nm size exhibited enhanced permeation across mucus and Caco-2 monolayer. In vivo pharmacokinetics study demonstrated that DEAE-DEX@LSDBC profoundly prolonged the circulation time and improved the oral absorption of both BER and CUR. Intriguingly, synchronized biodistribution of BER and CUR and highest biodistribution at liver was achieved by DEAE-DEX@LSDBC, which contributed to the optimal ameliorative effects on NAFLD. It was further verified to be mainly mediated by anti-oxidation and anti-inflammation related pathways CONCLUSION: DEAE-DEX coated bilosome displayed promoted oral absorption, prolonged circulation and synchronized biodistribution of BER and CUR, leading to improved ameliorative effects on NAFLD in mice, which provided a promising strategy for oral administration of drug combinations.