A novel deformable liposomal hydrogel loaded with a SREBP-1-inhibiting polypeptide for reducing sebum synthesis in golden hamster model.

Excessive sebum is the major factor involved in the pathophysiology of seborrheic diseases. Chemical medicines can result in mild to severe side effects. Polypeptides with much less side effects make them ideal for reducing sebum synthesis. Sterol regulatory element-binding proteins-1 (SREBP-1) is necessary for the biosynthesis of sterols. A SREBP-1-inhibiting polypeptide (SREi), which competitively inhibits the ubiquitination of Insig-1 so as to suppress the activation of SREBP-1 was selected as an active ingredient and formulated into skin topical preparations. The SREi anionic deformable liposomes contained sodium deoxycholate (SDCh) at the concentration of 4.4 mg/mL (SREi-ADL3) and SREi-ADL3 in 0.3% (w/v) carbomer hydrogel (SREi-ADL3-GEL) were prepared and characterized. The SREi-ADL3 presented a high entrapment efficiency of 92.62 ± 6.32%, a particle size of 99.54 ± 7.56 nm and a surface charge of -19.18 ± 0.45 mV. SREi-ADL3-GEL exhibited a sustained release behavior, a higher stability, a much more cellular uptake ability and transdermal absorption. In vivo golden hamster model confirmed that SREi-ADL3-GEL presented the strongest inhibitory effect on sebaceous gland growth and sebum synthesis by down-regulating the mRNA and protein expression of SREBP-1, fatty acid synthase (FAS) and acetyl-coenzyme A carboxylase 1 (ACC1). As confirmed by histological analysis, only a small amount of sebaceous gland lobes with the lightest staining intensity and the smallest dyeing area could be observed in the SREi-ADL3-GEL group. Taken together, SREi-ADL3-GEL displayed potential applications in sebum excessive production related diseases.

A novel estrogen-targeted PEGylated liposome co-delivery oxaliplatin and paclitaxel for the treatment of ovarian cancer.

Ovarian cancer is the second cause of death among gynecological malignancies. In this study, we designed a novel estrogen-targeted PEGylated liposome loaded with oxaliplatin and paclitaxel (ES-SSL-OXA/PTX) which could target estrogen receptor (ER) highly expressed on the surface of SKOV-3 cells to enhance therapeutic efficacy and reduce the side effects for SKOV-3 tumor therapy. ES-SSL-OXA/PTX was prepared by thin film hydration method and exhibited a uniform spherical morphology. Encapsulation efficiency (EE) were determined by HPLC method with the results of 44.10% for OXA and 65.85% for PTX. The mean particle size and polydispersity index (PDI) were 168.46 nm and 0.145, respectively. In vivo and in vitro targeting study confirmed that ES-SSL-OXA/PTX has optimum specific targeting ability. Meanwhile, In vitro and in vivo antitumor results of ES-SSL-OXA/PTX exhibited a superior antiproliferative effect on SKOV-3 cells and a stronger anti-tumor efficacy with the tumor inhibition rate of 85.24%. The pharmacokinetics results of ES-SSL-OXA/PTX showed a prolonged half-life time and a slowed clearance rate. The preliminary safety study of acute toxicity and long-term toxicity demonstrated ES-SSL-OXA/PTX exhibited a reduced toxicity profile. Based on the above results, ES-SSL-OXA/PTX could be a promising novel formulation for the treatment of ovarian cancer in future clinic.

Estrone-Conjugated PEGylated Liposome Co-Loaded Paclitaxel and Carboplatin Improve Anti-Tumor Efficacy in Ovarian Cancer and Reduce Acute Toxicity of Chemo-Drugs.

Purpose: Ovarian cancer is the most lethal gynecologic malignancy. The combination of paclitaxel (PTX) and carboplatin (CBP) is the first-line remedy for clinical ovarian cancer. However, due to the limitations of adverse reaction and lacking of targeting ability, the chemotherapy of ovarian cancer is still poorly effective. Here, a novel estrone (ES)-conjugated PEGylated liposome co-loaded PTX and CBP (ES-PEG-Lip-PTX/CBP) was designed for overcoming the above disadvantages. Methods: ES-PEG-Lip-PTX/CBP was prepared by film hydration method and could recognize estrogen receptor (ER) over-expressing on the surface of SKOV-3 cells. The characterizations, stability and in vitro release of ES-PEG-Lip-PTX/CBP were studied. In vitro cellular uptake and its mechanism were observed by fluorescence microscope. In vivo targeting effect in tumor-bearing mice was determined. Pharmacokinetics and biodistribution were studied in ICR mice. In vitro cytotoxicity and in vivo anti-tumor efficacy were evaluated on SKOV-3 cells and tumor-bearing mice, respectively. Finally, the acute toxicity in ICR mice was explored for assessing the preliminary safety of ES-PEG-Lip-PTX/CBP. Results: Our results showed that ES-PEG-Lip-PTX/CBP was spherical shape without aggregation. ES-PEG-Lip-PTX/CBP exhibited the optimum targeting effect on uptake in vitro and in vivo. The pharmacokinetics demonstrated ES-PEG-Lip-PTX/CBP had improved the pharmacokinetic behavior. In vitro cytotoxicity showed that ES-PEG-Lip-PTX/CBP maximally inhibited SKOV-3 cell proliferation and its IC50 values was 1.6 times lower than that of non-ES conjugated liposomes at 72 h. The in vivo anti-tumor efficacy study demonstrated that ES-PEG-Lip-PTX/CBP could lead strong SKOV-3 tumor growth suppression with a tumor volume inhibitory rate of 81.8%. Meanwhile, acute toxicity studies confirmed that ES-PEG-Lip-PTX/CBP significantly reduced the toxicity of the chemo drugs. Conclusion: ES-PEG-Lip-PTX/CBP was successfully prepared with an optimal physicochemical and ER targeting property. The data of pharmacokinetics, anti-tumor efficacy and safety study indicated that ES-PEG-Lip-PTX/CBP could become a promising therapeutic formulation for human ovarian cancer in the future clinic.

Estrone-targeted PEGylated Liposomal Nanoparticles for Cisplatin (DDP) Delivery in Cervical Cancer.

Cisplatin (DDP), a first-line chemo-drug for cervical cancer therapy, has limited the clinical use due to its high-dose administration and strong side effects. In this study, estrone-targeted PEGylated Liposomal DDP (ES-SSL-DDP) was prepared by thin-film hydration method and characterized. ES-SSL-DDP presented a spherical structure, with a particle size of about 97.3 nm, a surface charge of -19 mV and a high encapsulation efficiency of 47.7%. ES-SSL-DDP showed higher stability with a lower leakage rate less than 10% at 4°C. In vitro cellular uptake and internalization mechanisms in HeLa cells showed that ES-SSL-DDP had a stronger cellular uptake which was mainly via caveolin-mediated endocytosis. In vivo targeting evaluation demonstrated ES-SSL-DDP could specifically accumulated into the tumor site of HeLa-bearing mice. Cytotoxicity test on HeLa cells demonstrated the stronger cytotoxic activity of ES-SSL-DDP by MTT assay. In vivo anti-tumor efficacy of ES-SSL-DDP in HeLa tumor-bearing mice exhibited the most effective tumor inhibition. Pharmacokinetics and biodistribution of ES-SSL-DDP presented an improved metabolic behavior of the DDP. The acute toxicity demonstrated that ES-SSL-DDP could increase the LD50 and reduce the myelosuppression in healthy ICR mice. ES-SSL-DDP could be a novel promising chemo-formulation for cervical cancer in the future clinic.