Rangrang Fan

Improving the anti-colon cancer activity of curcumin with biodegradable nano-micelles

Curcumin (Cur) showed an antitumor effect by anti-angiogenesis and the induction of apoptosis. However, curcumin is limited in clinical applications by its hydrophobicity. Therefore, improving the water-solublilty and antitumor effect of curcumin are very meaningful. In this work, biodegradable monomethoxy poly(ethylene glycol)poly(lactide) copolymer (MPEG-PLA) micelles were employed to deliver curcumin by a self-assembly method. The obtained curcumin loaded polymeric micelles (Cur/MPEG-PLA) with a drug loading of 8% were monodisperse and ∼30 nm in diameter, which could release curcumin in an extended period in vitro and in vivo. In addition, Cur/MPEG-PLA showed a larger effect on cell growth inhibition and the induction of cell apoptosis than free curcumin in vitro. Furthermore, the therapy efficiency of Cur/MPEG-PLA on a colon cancer mouse model was evaluated in detail. Cur/MPEG-PLA could cause a more significant inhibitory effect on colon tumor growth than free curcumin with the same dose (P < 0.05 or P < 0.05, respectively), which indicated that Cur/MPEG-PLA could improve the antitumor effect of curcumin in vivo. Immunohistochemical and immunofluorescent analysis showed that Cur/MPEG-PLA could induce more tumor cell apoptosis, and inhibit more angiogenesis than the free drug group. Besides, Cur/MPEG-PLA exhibited a larger anti-angiogenesis effect in vivo. Finally, the anti-lung metastasis efficiency of Cur/MPEG-PLA on the colon cancer model was evaluated. Cur/MPEG-PLA could cause a more significant inhibitory effect on lung metastasis than free curcumin with the same dose (P < 0.05), which indicates that Cur/MPEG-PLA could improve the anti-lung metastasis effect of curcumin in vivo. Our data suggested Cur/MPEG-PLA may have potential clinical applications in colon cancer therapy.

PLA/F68/dexamethasone implants prepared by hot-melt extrusion for controlled release of anti-inflammatory drug to implantable medical devices: I. Preparation, characterization and hydrolytic degradation study.

Dexamethasone (Dex)-loaded implants were prepared by poly(d,l-lactic acid) (PLA) and poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) copolymer (PEG-PPG-PEG, Pluronic F68) using hot-melt extrusion method. The purpose of this research was to develop a hot-melt extruded implant PLA/F68/Dex for controlling release of Dex at the implant site. Drug loading and encapsulation efficiency were determined by UV spectrophotometer analysis. The maximum value of the drug loading and encapsulation efficiency for the implants was up to 48.9% and 97.9%, respectively. Differential scanning calorimetry was used to evaluate stability and interaction between the implant and drug. We had studied the water uptake of PLA/F68 implants kept constant at about 12% due to the water was absorbed to a large extent. Dex release profile in vitro was studied, and the results showed that the maximum value of the release rate was approximately 20%. The degradation behavior was confirmed by mass loss and scanning electron microscopy. In addition, the in vivo biocompatibility study indicated that the implants had no negative influence as a foreign material in the body response.

EGF and curcumin co-encapsulated nanoparticle/hydrogel system as potent skin regeneration agent.

Wound healing is a complex multifactorial process that relies on coordinated signaling molecules to succeed. Epidermal growth factor (EGF) is a mitogenic polypeptide that stimulates wound repair; however, precise control over its application is necessary to reduce the side effects and achieve desired therapeutic benefits. Moreover, the extensive oxidative stress during the wound healing process generally inhibits repair of the injured tissues. Topical applications of antioxidants like curcumin (Cur) could protect tissues from oxidative damage and significantly improve tissue remodeling. To achieve much accelerated wound healing effects, we designed a novel dual drug co-loaded in situ gel-forming nanoparticle/hydrogel system (EGF-Cur-NP/H) which acted not only as a supportive matrix for the regenerative tissue, but also as a sustained drug depot for EGF and Cur. In the established excisional full-thickness wound model, EGF-Cur-NP/H treatment significantly enhanced wound closure through increasing granulation tissue formation, collagen deposition, and angiogenesis, relative to normal saline, nanoparticle/hydrogel (NP/H), Cur-NP/H, and EGF-NP/H treated groups. In conclusion, this study provides a biocompatible in situ gel-forming system for efficient topical application of EGF and Cur in the landscape of tissue repair.

Injectable thermosensitive hydrogel composite with surface-functionalized calcium phosphate as raw materials

In this study, L-lactide was used to modify the tricalcium phosphate (β-TCP) and tetracalcium phosphate (TTCP) surface which can form functionalized poly(l-lactic acid) (PLLA)-grafted β-TCP (g-β-TCP) and PLLA-grafted TTCP (g-TTCP) particles. The g-β-TCP and g-TTCP obtained were incorporated into a PEG-PCL-PEG (PECE) matrix to prepare injectable thermosensitive hydrogel composites. The morphology of the hydrogel composites showed that the g-β-TCP and g-TTCP particles dispersed homogeneously into the polymer matrix, and each hydrogel composite had a three-dimensional network structure. Rheologic analysis showed that the composite had good thermosensitivity. Changes in calcium concentration and pH in simulated body fluid solutions confirmed the feasibility of surface-functionalized calcium phosphate for controlled release of calcium. All the results indicate that g-β-TCP/PECE and g-TTCP/PECE hydrogels might be a promising protocol for tissue engineering.

Preparation and characterization of polylactide/poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) hybrid fibers for potential application in bone tissue engineering

The aim of this study was to develop a kind of osteogenic biodegradable composite graft consisting of human placenta-derived mesenchymal stem cell (hPMSC) material for site-specific repair of bone defects and attenuation of clinical symptoms. The novel nano- to micro-structured biodegradable hybrid fibers were prepared by electrospinning. The characteristics of the hybrid membranes were investigated by a range of methods, including Fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry. Morphological study with scanning electron microscopy showed that the average fiber diameter and the number of nanoscale pores on each individual fiber surface decreased with increasing concentration of poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCEC). The prepared polylactide (PLA)/PCEC fibrous membranes favored hPMSC attachment and proliferation by providing an interconnected, porous, three-dimensional mimicked extracellular environment. What is more, hPMSCs cultured on the electrospun hybrid PLA/PCEC fibrous scaffolds could be effectively differentiated into bone-associated cells by positive alizarin red staining. Given the good cellular response and excellent osteogenic potential in vitro, the electrospun PLA/PCEC fibrous scaffolds could be one of the most promising candidates for bone tissue engineering.

In situ gel-forming AP-57 peptide delivery system for cutaneous wound healing.

In situ gel-forming system as local drug delivery system in dermal traumas has generated a great interest. Accumulating evidence shows that antimicrobial peptides play pivotal roles in the process of wound healing. Here in this study, to explore the potential application of antimicrobial peptide in wound healing, biodegradable poly(L-lactic acid)-Pluronic L35-poly(L-lactic acid) (PLLA-L35-PLLA) was developed at first. Then based on this polymer, an injectable in situ gel-forming system composed of human antimicrobial peptides 57 (AP-57) loaded nanoparticles and thermosensitive hydrogel was prepared and applied for cutaneous wound healing. AP-57 peptides were enclosed with biocompatible nanoparticles (AP-57-NPs) with high drug loading and encapsulation efficiency. AP-57-NPs were further encapsulated in a thermosensitive hydrogel (AP-57-NPs-H) to facilitate its application in cutaneous wound repair. As a result, AP-57-NPs-H released AP-57 in an extended period and exhibited quite low cytotoxicity and high anti-oxidant activity in vitro. Moreover, AP-57-NPs-H was free-flowing liquid at room temperature, and can form non-flowing gel without any crosslink agent upon applied on the wounds. In vivo wound healing assay using full-thickness dermal defect model of SD rats indicated that AP-57-NPs-H could significantly promote wound healing. At day 14 after operation, AP-57-NPs-H treated group showed nearly complete wound closure of 96.78 ± 3.12%, whereas NS, NPs-H and AP-57-NPs group recovered by about 68.78 ± 4.93%, 81.96 ± 3.26% and 87.80 ± 4.62%, respectively. Histopathological examination suggested that AP-57-NPs-H could promote cutaneous wound healing through enhancing granulation tissue formation, increasing collagen deposition and promoting angiogenesis in the wound tissue. Therefore, AP-57-NPs-H might have potential application in wound healing.

Enhanced antitumor effects by docetaxel/LL37-loaded thermosensitive hydrogel nanoparticles in peritoneal carcinomatosis of colorectal cancer

Intraperitoneal chemotherapy was explored in clinical trials as a promising strategy to improve the therapeutic effects of chemotherapy. In this work, we developed a biodegradable and injectable drug-delivery system by coencapsulation of docetaxel (Doc) and LL37 peptide polymeric nanoparticles (Doc+LL37 NPs) in a thermosensitive hydrogel system for colorectal peritoneal carcinoma therapy. Firstly, polylactic acid (PLA)-Pluronic L35-PLA (PLA-L35-PLA) was explored to prepare the biodegradable Doc+LL37 NPs using a water-in-oil-in-water double-emulsion solvent-evaporation method. Then, biodegradable and injectable thermosensitive PLA-L64-PLA hydrogel with lower sol–gel transition temperature at around body temperature was also prepared. Transmission electron microscopy revealed that the Doc+LL37 NPs formed with the PLA-L35-PLA copolymer were spherical. Fourier-transform infrared spectra certified that Doc and LL37 were encapsulated successfully. X-ray diffraction diagrams indicated that Doc was encapsulated amorphously. Intraperitoneal administration of Doc+LL37 NPs–hydrogel significantly suppressed the growth of HCT116 peritoneal carcinomatosis in vivo and prolonged the survival of tumor-bearing mice. Our results suggested that Doc+LL37 NPs–hydrogel may have potential clinical applications.

Novel nanoscale topography on poly(propylene carbonate)/poly(ε-caprolactone) electrospun nanofibers modifies osteogenic capacity of ADCs

In this study, we electrospun novel poly(propylene carbonate)/poly(e-caprolactone) (PPC/PCL) nanofibers with a special nanoscale topography using a simple process. The characteristics of the fabricated scaffolds were investigated using Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction analyses (XRD), thermogravimetric analyses (TG), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), water contact angle measurements (WCA), tensile tests and Brunauer–Emmett–Teller (BET) surface area analysis. To determine whether the nanoscale topography altered mesenchyme stem cell adhesion proliferation and differentiation behavior, adipose tissue-derived stromal cells (ADCs) were cultured on pure PPC electrospun scaffolds with smooth nanotopography and PPC/PCL (20 wt% PCL) hybrid scaffold with nanoscale topography. The results reveal that PPC/PCL electrospun fibers with special inter-surface-connected pores possess a high BET surface area and could promote ADCs adhesion and proliferation. According to alizarin red S staining and von-Kossa staining assays, there are more calcium nodule deposits on scaffolds with inter-surface-connected pores.

Docetaxel load biodegradable porous microspheres for the treatment of colorectal peritoneal carcinomatosis.

Micro- and nanoparticle formulations are widely used to improve the bioavailability of low solubility drugs. In this study, biodegradable poly(L-lactide acid)-Pluronic L121-poly(L-lactide acid) (PLLA-L121-PLLA) was developed. And then a controlled drug delivery system (CDDS), docetaxel (DOC) loaded PLLA-L121-PLLA porous microsphere (DOC MS) was prepared for colorectal peritoneal carcinomatosis (CRPC) therapy. DOC MS was prepared by DOC and PLLA-L121-PLLA using an oil-in-water emulsion solvent evaporation method. The particle size, morphological characteristics, encapsulation efficiency, in vitro drug release studies and in vitro cytotoxicity of DOC MS have been investigated. In vitro release profile demonstrated a significant difference between rapid release of free DOC and much slower and sustained release of DOC MS. Furthermore, cytotoxicity assay indicated cytotoxicity was increased after DOC was encapsulated into polymeric microspheres. In addition, intraperitoneal administration of DOC MS could effectively suppress growth and metastasis of CT26 peritoneal carcinomatosis in vivo, and prolonged the survival of tumor bearing mice. Immunohistochemistry staining of tumor tissues with Ki-67 revealed that DOC MS induced a stronger anti-tumor effect by increasing apoptosis of tumor cells in contrast to other groups (P<0.05). Thus, our results suggested that DOC MS may have great potential applications in clinic.

Nanofibers for improving the wound repair process: the combination of a grafted chitosan and an antioxidant agent

Wound healing, a complex process involving several important biomolecules and pathways, requires efficient dressings to enhance the therapy effects. Electrospinning nanofiber mats for wound healing have attracted significant interest because of their unique properties including ultrathin diameters, high volume ratios, and three-dimensional structure that mimics the extracellular matrix. In this study, we synthesized grafted chitosans with improved solubility, resulting in circumventing the use of acidic solvents, such as acetic acid and trifluoroacetic acid, simplified the electrospinning processes and fabricated poly(vinyl alcohol)-free nanofibers. The model drug curcumin was encapsulated in the nanofibers, consisting of grafted chitosan and poly(propylene carbonate), by electrospinning, which gradually released the drug from the matrix in 288 hours. Moreover, the curcumin-loaded composite nanofibers showed excellent free-radical scavenging capabilities. The enhanced wound healing efficacy was confirmed by an in vivo test and approximately 100% wound closure ratio was observed in the 10% curcumin-loaded PPC/g-CS nanofibers group at day 21 post surgery, which was subsequently evidenced by haematoxylin and eosin stain and Massons trichrome stain. Higher granulation scores and higher collagen contents were observed in the PPC/g-CS 10% curcumin group, showing significant differences among all the groups. These results demonstrated that the combination of grafted chitosan and curcumin improved the wound healing process. Moreover, electrospinning nanofibers based on the grafted polymer and curcumin showed potential for wound repair applications.