The endocytosis and intracellular fate of nanomedicines: Implication for rational design

AbstractNanomedicines employ multiple endocytic pathways to enter cells. Their following fate is interesting, but it is not sufficient understood currently. This review introduces the endocytic pathways, presents new technologies to confirm the specific endocytic pathways and discusses factors for pathway selection. In addition, some intriguing implication about nanomedicine design based on endocytosis will also be discussed at the end. This review may provide new thoughts for the design of novel multifunctional nanomedicines

Design, Synthesis, and Characterization of Schiff Base Bond-Linked pH-Responsive Doxorubicin Prodrug Based on Functionalized mPEG-PCL for Targeted Cancer Therapy

The side effects of doxorubicin (DOX) extremely limit its application in the treatment of malignant tumors. Nano-sized polymeric drugs based on the acidic microenvironment of tissular- or intra- tumor have attracted ample attention because of their potential in reducing side effects. In this research, an amphiphilic diblock copolymer based on poly (ethylene glycol) (PEG) and functionalized polycaprolactone (PCL) was synthesized and utilized as the drug carrier. DOX was chemically conjugated with the polymer via acid-cleavable imine bonds to obtain a novel pH-sensitive DOX prodrug (mPEG-PCL-Imi-DOX). mPEG-PCL-Imi-DOX (24.2 wt % DOX content) formed micelles with an average diameter of 125 nm through a simple solvent evaporation method. The in vitro release profile demonstrated that DOX release of the prodrug micelles was pH-responsive and able to be accelerated with the decrease of pH. In vitro cytotoxicity assay tests revealed that the pH-sensitive DOX prodrug micelles exhibited relatively lower toxicity and similar antitumor efficacy towards MCF-7 cells compared with free DOX. Hence, the DOX prodrug micelles with imine bonds can offer a carrier with great potential for chemo-therapeutics

Electrospun nanofibers as a wound dressing for treating diabetic foot ulcer

Abstracts: Diabetes is one of the most prevalent diseases in the world with high-mortality and complex complications including diabetic foot ulcer (DFU). It has been reported that the difficulties in repairing the wound related to DFU has much relationship with the wound infection, change of inflammatory responses, lack of extracellular matrix (ECM), and the failure of angiogenesis. Following the development of medical materials and pharmaceutical technology, nanofibers has been developed by electrospinning with huge porosity, excellent humidity absorption, a better oxygen exchange rate, and some antibacterial activities. That is to say, as a potential material, nanofibers must be a wonderful candidate for the DFU treatment with so many benefits. Careful selection of polymers from natural resource and synthetic resource can widen the nanofibrous application. Popular methods applied for the nanofibrous fabrication consist of uniaxial electrospinning and coaxial electrospinning. Furthermore, nanofibers loading chemical, biochemical active pharmaceutical ingredient (API) or even stem cells can be wonderful dosage forms for the treatment of DFU. This review summarizes the present techniques applied in the fabrication of nanofibrous dressing (ND) that utilizes a variety of materials and active agents to offer a better health care for the patients suffering from DFU. Keywords: Nanofibers, Nanofibrous dressing, Diabetic foot ulcer, Uniaxial electrospinning, Coaxial electrospinnin

Pharmacokinetic performance of the nitrendipine intravenous submicron emulsion in rats

AbstractTo compare pharmacokinetic behaviors of nitrendipine submicron emulsion with nitrendipine solution following intravenous administration in rats. The plasma concentrations were analyzed by ultra-performance liquid chromatography coupled with tandem mass spectrometry detection (UPLC–MS/MS) through a new validated method. The pharmacokinetic parameters of the nitrendipine submicron emulsion and nitrendipine solution were as follows: AUC0–t 900.76 ± 186.59 versus 687.08 ± 66.24 ng h/ml, Cmax 854.54 ± 159.48 versus 610.59 ± 235.99 ng/ml, t1/2 2.37 ± 1.99 versus 2.80 ± 2.69 h. The relative bioavailability of nitrendipine submicron emulsion to nitrendipine solution was 131.4 ± 11.3%. The developed methods could meet the requirements of bioanalysis. Compared to the solution injection, intravenous submicron emulsion presents higher systematic exposure which can help to improve the therapeutic efficacy

Design, Synthesis, and Characterization of Schiff Base Bond-Linked pH-Responsive Doxorubicin Prodrug Based on Functionalized mPEG-PCL for Targeted Cancer Therapy

The side effects of doxorubicin (DOX) extremely limit its application in the treatment of malignant tumors. Nano-sized polymeric drugs based on the acidic microenvironment of tissular- or intra- tumor have attracted ample attention because of their potential in reducing side effects. In this research, an amphiphilic diblock copolymer based on poly (ethylene glycol) (PEG) and functionalized polycaprolactone (PCL) was synthesized and utilized as the drug carrier. DOX was chemically conjugated with the polymer via acid-cleavable imine bonds to obtain a novel pH-sensitive DOX prodrug (mPEG-PCL-Imi-DOX). mPEG-PCL-Imi-DOX (24.2 wt % DOX content) formed micelles with an average diameter of 125 nm through a simple solvent evaporation method. The in vitro release profile demonstrated that DOX release of the prodrug micelles was pH-responsive and able to be accelerated with the decrease of pH. In vitro cytotoxicity assay tests revealed that the pH-sensitive DOX prodrug micelles exhibited relatively lower toxicity and similar antitumor efficacy towards MCF-7 cells compared with free DOX. Hence, the DOX prodrug micelles with imine bonds can offer a carrier with great potential for chemo-therapeutics

Acetal-Linked Paclitaxel Polymeric Prodrug Based on Functionalized mPEG-PCL Diblock Polymer for pH-Triggered Drug Delivery

The differences in micro-environment between cancer cells and the normal ones offer the possibility to develop stimuli-responsive drug-delivery systems for overcoming the drawbacks in the clinical use of anticancer drugs, such as paclitaxel, doxorubicin, and etc. Hence, we developed a novel endosomal pH-sensitive paclitaxel (PTX) prodrug micelles based on functionalized poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) diblock polymer with an acid-cleavable acetal (Ace) linkage (mPEG-PCL-Ace-PTX). The mPEG-PCL-Ace-PTX5 with a high drug content of 23.5 wt % was self-assembled in phosphate buffer (pH 7.4, 10 mM) into nanosized micelles with an average diameter of 68.5 nm. The in vitro release studies demonstrated that mPEG-PCL-Ace-PTX5 micelles was highly pH-sensitive, in which 16.8%, 32.8%, and 48.2% of parent free PTX was released from mPEG-PCL-Ace-PTX5 micelles in 48 h at pH 7.4, 6.0, and 5.0, respectively. Thiazolyl Blue Tetrazolium Bromide (MTT) assays suggested that the pH-sensitive PTX prodrug micelles displayed higher therapeutic efficacy against MCF-7 cells compared with free PTX. Therefore, the PTX prodrug micelles with acetal bond may offer a promising strategy for cancer therapy

The effect of lengths of branched-chain fatty alcohols on the efficacy and safety of docetaxel-prodrug nanoassemblies

The self-assembly prodrugs are usually consisted of drug modules, activation modules, and assembly modules. Keeping the balance between efficacy and safety by selecting suitable modules remains a challenge for developing prodrug nanoassemblies. This study designed four docetaxel (DTX) prodrugs using disulfide bonds as activation modules and different lengths of branched-chain fatty alcohols as assembly modules (C16, C18, C20, and C24). The lengths of the assembly modules determined the self-assembly ability of prodrugs and affected the activation modules' sensitivity. The extension of the carbon chains improved the prodrugs’ self-assembly ability and pharmacokinetic behavior while reducing the cytotoxicity and increased cumulative toxicity. The use of C20 can balance efficacy and safety. These results provide a great reference for the rational design of prodrug nanoassemblies

Inhibition of post-surgery tumour recurrence via a sprayable chemo-immunotherapy gel releasing PD-L1 antibody and platelet-derived small EVs

Background Melanoma is the most serious type of skin cancer, and surgery is an effective method to treat melanoma. Unfortunately, local residual micro-infiltrated tumour cells and systemic circulating tumour cells (CTCs) are significant causes of treatment failure, leading to tumour recurrence and metastasis. Methods Small EVs were isolated from platelets by differential centrifugation, and doxorubicin-loaded small EVs (PexD) was prepared by mixing small EVs with doxorubicin (DOX). PexD and an anti-PD-L1 monoclonal antibody (aPD-L1) were co-encapsulated in fibrin gel. The synergistic antitumour efficacy of the gel containing PexD and aPD-L1 was assessed both in vitro and in vivo. Results Herein, we developed an in situ-formed bioresponsive gel combined with chemoimmunotherapeutic agents as a drug reservoir that could effectively inhibit both local tumour recurrence and tumour metastasis. In comparison with a DOX solution, PexD could better bind to tumour cells, induce more tumour immunogenic cell death (ICD) and promote a stronger antitumour immune response. PexD could enter the blood circulation through damaged blood vessels to track and eliminate CTCs. The concurrent release of aPD-L1 at the tumour site could impair the PD-1/PD-L1 pathway and restore the tumour-killing effect of cytotoxic T cells. This chemoimmunotherapeutic strategy triggered relatively strong T cell immune responses, significantly improving the tumour immune microenvironment. Conclusion Our findings indicated that the immunotherapeutic fibrin gel could “awaken” the host innate immune system to inhibit both local tumour recurrence post-surgery and metastatic potential, thus, it could serve as a promising approach to prevent tumour recurrence.ISSN:1477-315

Rational Engineering Docetaxel Prodrug Nanoassemblies: Response Modules Guiding Efficacy Enhancement and Toxicity Reduction

Prodrug-based nanoassemblies have been developed to solve the bottlenecks of chemotherapeutic drugs. The fabricated prodrugs usually consist of active drug modules, response modules, and modification modules. Among three modules, the response modules play a vital role in controlling the intelligent drug release at tumor sites. Herein, various locations of disulfide bond linkages were selected as response modules to construct three Docetaxel (DTX) prodrugs. Interestingly, the small structural difference caused by the length of response modules endowed corresponding prodrug nanoassemblies with unique characteristic. α-DTX-OD nanoparticles (NPs) possessed the advantages of high redox-responsiveness due to their shortest linkages. However, they were too sensitive to retain the intact structure in the blood circulation, leading to severe systematic toxicity. β-DTX-OD NPs significantly improved the pharmacokinetics of DTX but may induce damage to the liver. In comparison, γ-DTX-OD NPs with the longest linkages greatly ameliorated the delivery efficiency of DTX as well as improved DTX’s tolerance dose