Application of carrier and plasticizer to improve the dissolution and bioavailability of poorly water-soluble baicalein by hot melt extrusion.

The objective of this study was to develop a suitable formulation for baicalein (a poorly water-soluble drug exhibiting high melting point) to prepare solid dispersions using hot melt extrusion (HME). Proper carriers and plasticizers were selected by calculating the Hansen solubility parameters, evaluating melting processing condition, and measuring the solubility of obtained melts. The characteristic of solid dispersions prepared by HME was evaluated. The dissolution performance of the extrudates was compared to the pure drug and the physical mixtures. Physicochemical properties of the extrudates were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FTIR). Relative bioavailability after oral administration in beagle dogs was assessed. As a result, Kollidon VA64 and Eudragit EPO were selected as two carriers; Cremophor RH was used as the plasticizer. The dissolution of all the extrudates was significantly improved. DSC and PXRD results suggested that baicalein in the extrudates was amorphous. FTIR spectroscopy revealed the interaction between drug and polymers. After oral administration, the relative bioavailability of solid dispersions with VA64 and EPO was comparative, about 2.4- and 2.9-fold greater compared to the pure drug, respectively.

Cancer-Cell-Biomimetic Nanoparticles for Targeted Therapy of Multiple Myeloma Based on Bone Marrow Homing.

Multiple myeloma (MM) is the second most common hematological malignancy. It is characterized by abnormal transformation and uncontrolled clonal proliferation of malignant plasma cells in the bone marrow (BM), which can destroy bone structure and inhibit hematopoiesis. Although there are new therapeutic methods, they are not curative, mainly because it is difficult to deliver an effective amount of drug to BM, leading to a failure to eradicate MM cells inside the BM. BM homing is an important and unique characteristic of MM cells and it is mainly affected by surface molecules on the tumor cell membrane. Inspired by this mechanism, an MM-mimicking nanocarrier is developed by coating bortezomib (BTZ)-loaded poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCEC) nanoparticles with the MM cell membrane. The MM-mimicking nanoparticles can enter the BM based on BM homing as a "Trojan horse" and target the tumor cells through homologous targeting. In this way, drug availability at the myeloma site is enhanced so as to inhibit MM growth. In addition, these MM-mimicking nanoparticles can escape phagocytosis by the MPS and have a long circulation effect. The in vivo therapeutic results demonstrate an excellent treatment efficacy for MM. Accordingly, this strategy may be a promising platform for the treatment of MM.

Preparation of Adenosine-Loaded Electrospun Nanofibers and Their Application in Bone Regeneration.

The possibility of composite nanofibers being able to regenerate bone is an attractive proposition. Adenosine, which occurs naturally in humans, has been shown to promote the osteogenic differentiation of mesenchymal stem cells (MSCs) and osteoprogenitor cells. In this study, electrospun nanofibers of poly(3-hydroxybutyrate-co-3-hydroxybutyrate) (PHBV) doped with adenosine were demonstrated to exhibit excellent capacity for bone regeneration, after optimization of the electrospinning process. The biomechanical properties, hydrophilicity, biocompatibility, cellular performance of the nanofibers and adenosine release profile from the composite nanofibers were evaluated. The osteogenic capacity of the composite nanofibers in vitro and in vivo was systematically studied. Electrospun adenosine/PHBV nanofibers demonstrated excellent tissue biocompatibility. In addition, adenosine-loaded/PHBV electrospun nanofibers exhibited substantial bone regeneration capacity in vitro and in critical-sized rabbit cranial defects in vivo, which was greater than that of bone marrow MSC (BMSC)-loaded/PHBV electrospun nanofibers. Additionally, BMSCs/PHBV electrospun nanofibers required culture with BMSCs for a period of time prior to surgery, whereas the adenosine/PHBV electrospun nanofibers could be implanted directly. To date, there is seldom no studies have evaluated the capability of bone regeneration of electrospun nanofibers doped with adenosine. Using a simple fabrication process and with a structure similar to that of natural extracellular matrix (ECM), electrospun adenosine/PHBV nanofibers exhibited excellent biocompatibility and osteogenic capacity. In addition, adenosine is inexpensive, straightforward to obtain and store and so holds huge practical potential in bone tissue engineering applications.

Redox/pH dual-stimuli responsive camptothecin prodrug nanogels for "on-demand" drug delivery.

At present, chemotherapy remains to be one of the most important therapeutic approaches for malignant tumors. The tumor microenvironment(TME)-responsive intelligent drug delivery systems are still the hot research topics in delivering chemotherapeutic drugs. Camptothecin (CPT) possesses very strong antitumor activities, but its clinical application is hindered by its poor water-solubility and serious toxic side effects. Herein, a new intelligent and TME-responsive P(CPT-MAA) prodrug nanogel was developed for delivering CPT and reducing its side effects. P(CPT-MAA) prodrug nanogels were prepared with methacrylic acid (MAA), CPT monomer (CPTM) and N,N'-methylenebisacrylamide (Bis) via distillation-precipitation polymerization, in which CPT was covalently conjugated into the nanogels via redox-responsive disulfide linker. The as-prepared nanogels were spherical shapes with uniform size and narrow size distribution. With the help of redox-responsive property of disulfide linker and pH-responsive property of PMAA, the release of CPT from prodrug nanogels was redox/pH-dual dependent and could be accelerated by the increased concentration of GSH and the decreased pH value, which were favorable to realize the "on-demand" drug release in tumor cell and tumor tissue microenvironment. Furthermore, P(CPT-MAA) prodrug nanogels exhibited superior antitumor activity both in vitro and in vivo without observed side effects. Hence, the prepared P(CPT-MAA) prodrug nanogels may be a promise delivery system for chemotherapeutic agents.

Oxygen-generating Hybrid Polymeric Nanoparticles with Encapsulated Doxorubicin and Chlorin e6 for Trimodal Imaging-Guided Combined Chemo-Photodynamic Therapy.

The combination of chemotherapy with photodynamic therapy (PDT) has attracted broad attention as it can overcome limitations of conventional chemo-treatment by using different modes of action. However, the efficacy of PDT to treat solid tumors is severely affected by hypoxia in tumors. Methods: In this study, we developed oxygen-generating theranostic nanoparticles (CDM NPs) by hierarchically assembling doxorubicin (DOX), chlorin e6 (Ce6) and colloidal manganese dioxide (MnO2) with poly (ε-caprolactone-co-lactide)-b-poly (ethylene glycol)-b-poly (ε-caprolactone-co-lactide) for treating breast cancer. The in vitro and in vivo antitumor efficacy and imaging performance were investigated. Results: The theranostic nanoparticles showed high stability and biocompatibility both in vitro and in vivo. MnO2 within the nanoparticles could trigger decomposition of excessive endogenous H2O2 in the tumor microenvironment to generate oxygen in-situ to relieve tumor hypoxia. With enhanced oxygen generation, the PDT effect was significantly improved under laser-irradiation. More importantly, this effect together with that of DOX was able to dramatically promote the combined chemotherapy-PDT efficacy of CDM NPs in an MCF-7 tumor-bearing mouse model. Furthermore, the real-time tumor accumulation of the nanocomposites could be monitored by fluorescence imaging, photoacoustic (PA) imaging and magnetic resonance imaging (MRI). Conclusion: The designed CDM NPs are expected to provide an alternative way of improving antitumor efficacy by combined chemo-PDT further enhanced by oxygen generation, and would have broad applications in cancer theranostics.

A low-molecular-weight heparin-coated doxorubicin-liposome for the prevention of melanoma metastasis.

Tumor metastasis is the biggest challenge in cancer therapy. During the metastasis process, metastatic cells could acquire stealth ability toward immune system through the formation of a protection cloak by hijacking platelets (PTs). Heparins, a heterogeneous mixture of glycosaminoglycans, can inhibit metastatic cascades by blocking P-selectin-mediated intercellular adhesion between tumor cells and PTs. In this study, low-molecular-weight heparin-coated doxorubicin-loaded liposome (LMWH-DOX-Lip) was developed for metastasis preventative therapy. The formation of LMWH-DOX-Lip was based on electrostatic interactions between the negatively charged heparins and cationic lipids. LMWH-DOX-Lip prepared at the optimum prescription possessed high entrapment efficiency, ideal particle size and zeta potential. Morphology of LMWH-DOX-Lip was characterized by atomic force microscopy and transmission electron microscopy. The results of confocal microscopic observations and flow cytometry analysis indicated that LMWH-DOX-Lip mediated an efficient cellular uptake in B16F10 melanoma cell line. Besides, LMWH-DOX-Lip displayed an increased cytotoxic over their unmodified counterparts. Furthermore, the inhibition effect of LMWH-DOX-Lip on adhesion between tumor cells and PTs/P-selectin was observed. In vivo study performed on a pulmonary melanoma mouse model revealed a substantially tumor metastasis prevention by LMWH-DOX-Lip. All these results suggested that LMWH-DOX-Lip could significantly inhibit metastasis through preventing the tumor cell-platelet interactions and in the meantime suppressed tumor growth.