Dopamine Delivery via pH-Sensitive Nanoparticles for Tumor Blood Vessel Normalization and an Improved Effect of Cancer Chemotherapeutic Drugs.

Tumor blood vessels have been reported to be abnormal in both structure and function compared with those in normal tissues, leading to a hostile microenvironment and inadequate antitumor drug delivery. Dopamine, a chemical messenger, is proven to inhibit angiogenesis and improve tumor vessel normalization. Here, a mesoporous silicon nanoparticle (MSN) is constructed that is responsive to the weakly acidic pH of the tumor extracellular matrix for steady delivery and tumor-localized release of dopamine. Then MSNs are functionalized with amine conjugated phenylboronicacid molecules, and dopamine is loaded by reacting with phenylboronic acid. In a weakly acidic environment, MSNs intelligently release dopamine due to the hydrolysis of boronic-ester bond between dopamine and phenylboronic acid, resulting in an evident inhibition of vascular endothelial cell migration and tubule formation. It is shown that loading of dopamine into the functional MSNs significantly prolong the circulatory half-life of this small molecule. After intravenous injection to tumor bearing mice, this nanoformulation induce tumor blood vessel normalization, thereby improving the antitumor chemotherapeutic efficacy of doxorubicin. This study demonstrates that the pH-responsive MSN offers great potential for delivery of dopamine in vivo and the normalization of tumor vessels by dopamine can provide an auxiliary treatment for cancer chemotherapeutic drugs.

Injectable Hexapeptide Hydrogel for Localized Chemotherapy Prevents Breast Cancer Recurrence.

Although postsurgical chemotherapy is frequently used for the treatment of breast cancer, tumor recurrence is still a frequent event. Enhancing the efficacy of chemotherapy via localized drug delivery may help to prevent breast cancer recurrence. To achieve this goal, we designed a hydrogel nanocarrier that could be injected at the tumor site by coassembly of tailor-made hexapeptide and doxorubicin. Evidently, on the basis of our findings, the sustained release of drug from the hydrogel led to a reduction in cancer recurrence, including the suppression of primary regrowth and distant metastasis. This localized chemotherapy strategy did not show any obvious side effects in vivo and represents a promising adjuvant therapeutic strategy for breast cancer recurrence.

Tumor Microenvironment Targeting and Responsive Peptide-Based Nanoformulations for Improved Tumor Therapy.

The tumor microenvironment participates in all stages of tumor progression and has emerged as a promising therapeutic target for cancer therapy. Rapid progress in the field of molecular self-assembly using various biologic molecules has resulted in the fabrication of nanoformulations that specifically target and regulate microenvironment components to inhibit tumor growth. This inhibition process is based on differentiating between biophysicochemical cues guiding tumor and normal tissue microenvironments. Peptides and peptide derivatives, owing to their biocompatibility, chemical versatility, bioactivity, environmental sensitivity, and biologic recognition abilities, have been widely used as building blocks to construct multifunctional nanostructures for targeted drug delivery and controlled release. Several groups of peptides have been identified as having the ability to penetrate plasma membranes, regulate the essential signaling pathways of angiogenesis and immune reactions, and recognize key components in the tumor microenvironment (such as vascular systems, stromal cells, and abnormal tumor biophysicochemical features). Thus, using different modules, various functional peptides, and their derivatives can be integrated into nanoformulations specifically targeting the tumor microenvironment with increased selectivity, on-demand response, elevated cellular uptake, and improved tumor therapy. In this review, we introduce several groups of functional peptides and highlight peptide-based nanoformulations that specifically target the tumor microenvironment. We also provide our perspective on the development of smart drug-delivery systems with enhanced therapeutic efficacy.

Assembly of hepatitis E vaccine by 'in situ' growth of gold clusters as nano-adjuvants: an efficient way to enhance the immune responses of vaccination.

Vaccine-based immunotherapy plays an integral role in the development of present and future clinical therapies. Despite the success, there is still a great need to improve the efficiency and safety of vaccines. Nanoparticles have been widely used for improving the efficacy of vaccines by encapsulating the vaccines or using nanoparticles as immune adjuvants. However, the methods for the preparation of nanoparticles are complex with a relatively low encapsulation efficiency of protein vaccine inside the nanocarriers and/or undefined physiochemical properties. Here, we report a new method of preparation of a vaccine by the "in situ" growth of gold clusters in the hepatitis E vaccine (HEVA). The gold cluster grafted HEVA (HEVA/Au) can be easily obtained and there is no loss of HEVA during the preparation process. More importantly, the "in situ" prepared HEVA/Au can not only enhance its immune responses in vivo, but also reduce the potential toxicity of HEVA. Furthermore, the intrinsic fluorescence of gold clusters enables the HEVA to be traceable, which may open a way to track the dynamic behavior of vaccines and further help to optimize an individual therapeutic regimen for immunotherapy.

Probing cell-matrix interactions in RGD-decorated macroporous poly (ethylene glycol) hydrogels for 3D chondrocyte culture.

Macroporous hydrogels have shown great promise as scaffolds for cartilage engineering by facilitating nutrition transport and tissue in growth. Cell-matrix adhesion-a fundamental process in tissue engineering-has shown a profound effect on subsequent cell phenotype, extracellular matrix (ECM) accumulation, and tissue reorganization. In this study, arginine-glycine-aspartic acid (RGD) was introduced to macroporous hydrogels of poly (ethylene glycol) (PEG) to fabricate PEG-G400 (with 0.4mM RGD) and PEG-G2000 (2mM RGD) to probe the cell-matrix interactions within hydrogels. Primary chondrocytes demonstrated a slightly stretched morphology with increasing RGD concentration and PEG-G2000 hydrogels boosted cell viability, proliferation, and deposition of collagen II and GAG, in comparison to the PEG-G400 and PEG-RED groups. Results also revealed chondrocytes within the cell aggregates underwent dedifferentiation and hypertrophy within RGD incorporated hydrogels, as evidenced by the high level of gene expression of collagen I on day 14 and strong immunohistological staining of collagen X and collagen I on day 35. Evidently, a high concentration of RGD (2mM RGD) enhanced cell-matrix interactions through elevating the expression of integrin ß1 and vinculin. Thus, the integration of RGD in macroporous hydrogels with a concentration of 2 mM may be sufficient for improving cell functionality, with a slight probability of dedifferentiation and hypertrophy of chondrocytes.

Practical execution of defect preparation prior to surgical cartilage intervention: results from a representative meeting survey among experts.

During a specialised orthopedic meeting held on 'the state of the art in cartilage defect repair', all previously fully-registered participants were requested to participate in an electronic survey by the use of a moderator-presented "Power Point Presentation-based" 9-item questionnaire. The aim of this survey was to assess indication, approach, and treatment execution of cartilage defect debridement prior to planned microfracture (MFX) or autologous chondrocyte implantation (ACI). All participants completed the questionnaire (n = 146) resulting in a return rate of 100 %. An uncertainty exists as to whether the removal of the calcifying layer prior to cartilage repair must be carried out or not. The same was true for the acceptability of subchondral bleeding prior to microfracturing and its handling prior to autologous chondrocyte implantation. There is a degree of unanimity among experts regarding the management of osteophytes and bone marrow edema. In a homogenous society collective of consultants that frequently deal with cartilage defective pathologies, there still remain a significant heterogeneity in selected topics of defect debridement.

Self-assembled octapeptide scaffolds for in vitro chondrocyte culture.

Nature has evolved a variety of creative approaches to many aspects of materials synthesis and microstructural control. Molecular self-assembly is a simple and efficient way to fabricate complex nanostructures such as hydrogels. We have recently investigated the gelation properties of a series of ionic-complementary peptides based on the alternation of non-polar hydrophobic and polar hydrophilic residues. In this work we focus on one specific octapeptide, FEFEFKFK (F, phenylalanine; E, glutamic acid; K, lysine). This peptide was shown to self-assemble in solution and form ß-sheet-rich nanofibres which, above a critical gelation concentration, entangle to form a self-supporting hydrogel. The fibre morphology of the hydrogel was analysed using transmission electron microscopy and cryo-scanning electron microscopy illustrating a dense fibrillar network of nanometer size fibres. Oscillatory rheology results show that the hydrogel possesses visco-elastic properties. Bovine chondrocytes were used to assess the biocompatibility of the scaffolds over 21 days under two-dimensional (2-D) and three-dimensional (3-D) cell culture conditions, particularly looking at cell morphology, proliferation and matrix deposition. 2-D culture resulted in cell viability and collagen type I deposition. In 3-D culture the mechanically stable gel was shown to support the viability of cells, the retention of cell morphology and collagen type II deposition. Subsequently the scaffold may serve as a template for cartilage tissue engineering.