Estrone-modified pH-sensitive Glycol Chitosan Nanoparticles for Drug Delivery in Breast Cancer

Publication date: Available online 14 April 2018
Source:Acta Biomaterialia
Author(s): Huan Yang, Cui Tang, Chunhua Yin
Estrone-modified glycol chitosan nanoparticles (GCNP-ES) based on the mechanisms of ES-mediated endocytosis and intracellular pH-responsive drug release were developed for the treatment of breast cancer. GCNP-ES were prepared by grafting copolymerization of glycol chitosan with 2-(diisopropylamino)ethyl methacrylate to generate GCNP prior to ES conjugation. The particle size, zeta potential, and paclitaxel (PTX) encapsulation efficiency of GCNP-ES were characterized. In particular, GCNP-ES exhibited pH-responsive dissociation properties while maintaining stability under long-term storage and lyophilization. The drug release of PTX-loaded GCNP-ES (PTX/GNCP-ES) was modestly prolonged with considerable pH sensitivity. GCNP-ES promoted internalization in breast cancer MCF-7 cells by approximately 5-fold as compared to GCNP, and the internalized GCNP-ES was mainly localized in the endosomes of MCF-7 cells. PTX/GNCP-ES exhibited higher cytotoxicity and cell apoptosis ratio than GCNP. In mice with MCF-7 breast cancer xenograft, PTX/GCNP-ES showed higher accumulation at the tumor site, which resulted in a higher tumor inhibition ratio (81.4%) than that achieved by PTX/GCNP (69.4%) and PTX solution (48.8%). Furthermore, no histological and hematological toxicity was detected in in vivo studies of PTX/GCNP-ES. Overall, these results suggested the potential applicability of GCNP-ES as a drug delivery system for breast cancer therapy.Statement of significanceMost breast cancers are hormone dependent. Herein, we developed a estrone-modified glycol chitosan nanoparticles (GCNP-ES) as a drug delivery system to overcome the drawbacks of chemotherpeutic drugs, including poor water solubility and lack of specifity. GCNP-ES could provide efficient drug delivery in breast cancer cells. The study demonstrated that GCNP-ES could dissociate under mildly acidic conditions, leading to the timely payload release of the drug in target tumor cells following internalization. The conjugated estrone of the nanoparticles could significantly increase drug accumulation in the tumor site and result in enhanced therapeutic effect. Thus, the potential applicability of GCNP-ES was suggested.

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Comparative adsorption profiles of basal lamina proteome and gingival cells onto dental and titanium surfaces

Publication date: Available online 13 April 2018
Source:Acta Biomaterialia
Author(s): Mohamed-Nur Abdallah, Ghada Abughanam, Simon D Tran, Zeeshan Sheikh, Mohamed A. Mezour, Tayebah basiri, Yizhi Xiao, Marta Cerruti, Walter L Siqueira, Faleh Tamimi
Titanium (Ti) dental implants are susceptible to bacterial infections and failure due to lack of proper epithelial seal. Epithelial cells establish a strong epithelial seal around natural teeth by the deposition of basal lamina (BL) proteins that adsorb on the tooth surface. This seal can even be re-established onto cementum or dentin following injury or periodontal therapy. However, it is unclear how tooth surfaces promote this cell attachment and protein adsorption. Understanding the interactions between BL proteins and epithelial cells with dentin and Ti will facilitate the development of implant surfaces that promote the formation of an epithelial seal and improve the success of periodontal therapy and wound healing on natural teeth. To study these interactions, we used a surface proteomic approach to decipher the adsorption profile of BL proteins onto Ti and dentin, and correlated these adsorption profiles with in vitro interactions of human gingival fibroblasts and epithelial cells. Results showed that dentin adsorbed higher amounts of key BL proteins, particularly laminin and nidogen-1, and promoted more favorable interactions with epithelial cells than Ti. Next, dentin specimens were deproteinized or partially demineralized to determine if its mineral or protein component was responsible for BL adsorption and cell attachment. Deproteinized (mineral-rich) and partially demineralized (protein-rich) dentin specimens revealed BL proteins (i.e. laminin and nidogen-1) and epithelial cells interact preferentially with dentinal proteins rather than dentin mineral. These findings suggest that, unlike Ti, dentin and, in particular, dentinal proteins have a selective affinity to BL proteins that enhance epithelial cell attachment.Statement of SignificanceIt is remains unclear why natural teeth, unlike titanium dental implants, promote the formation of an epithelial seal that protects them against the external environment. This study used a surface screening approach to analyze the adsorption of proteins produced by epithelial tissues onto tooth-dentin and titanium surfaces, and correlate it with the behaviour of cells. This study shows that tooth-dentin, in particular its proteins, has a higher selective affinity to certain adhesion proteins, and subsequently allows more favourable interactions with epithelial cells than titanium. This knowledge could help in developing new approaches for re-establishing and maintaining the epithelial seal around teeth, and could pave the way for developing implants with surfaces that allow the formation of a true epithelial seal.

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3D-printed scaffolds with bioactive elements-induced photothermal effect for bone tumor therapy

Publication date: Available online 13 April 2018
Source:Acta Biomaterialia
Author(s): Yaqin Liu, Tao Li, Hongshi Ma, Dong Zhai, Cuijun Deng, Jinwu Wang, Shangjun Zhuo, Jiang Chang, Chengtie Wu
For treatment of bone tumor and regeneration of bone defects, the biomaterials should possess the ability to kill tumor cells and regenerate bone defect simultaneously. To date, there are a few biomaterials possessing such dual functions, the disadvantages, however, such as long-term toxicity and degradation, restrict their application. Although bioactive elements have been incorporated into biomaterials to improve their osteogenic activity, there is no report about elements-induced functional scaffolds for photothermal tumor therapy. Herein, the elements (Cu, Fe, Mn, Co)-doped bioactive glass-ceramic (BGC) scaffolds with photothermal effect and osteogenic differentiation ability were prepared via 3D-printing method. Moreover, the photothermal anti-tumor effect and osteogenic activity of these scaffolds were systematically investigated. The prepared elements-doped scaffolds possessed excellent photothermal performance, which displayed a trend, 5Cu-BGC > 5Fe-BGC > 5Mn-BGC > 5Co-BGC, in this study. The final temperature of elements-doped scaffolds can be well controlled by altering the doping element categories, contents and laser power density. Additionally, the hyperthermia induced by 5Cu-BGC, 5Fe-BGC and 5Mn-BGC effectively killed tumor cells in vitro and inhibited tumor growth in vivo. More importantly, 5Fe-BGC and 5Mn-BGC scaffolds could promote rabbit bone mesenchymal stem cells (rBMSCs) adhesion, and the ionic products released from elements-doped scaffolds significantly stimulated the osteogenic differentiation of bone-forming cells. These results suggested that 5Fe-BGC and 5Mn-BGC scaffolds possessed promising potential for photothermal treatment of bone tumor and at the same time for stimulating bone regeneration, representing a smart strategy for the treatment of bone tumors by combining dual functional bioactive ions with tissue engineering scaffolds.Statement of significanceThe major innovation of this study is that we fabricated the elements (Cu, Fe, Mn, Co)-doped bioactive scaffolds via 3D printing technique and found that they possess distinct photothermal performance and osteogenic differentiation ability. To the best of our knowledge, there is no report about elements-doped scaffolds for photothermal therapy of bone tumor. This is an important research advance by combining the photothermal effect and osteogenic differentiation activity of bioactive elements in the scaffold system for potential bone tumor therapy and bone reconstruction. We optimized the elements-doped scaffolds and found the photothermal effect of elements-doped scaffolds (5Cu-BGC, 5Fe-BGC, 5Mn-BGC) could effectively kill tumor cells in vivo. The photothermal performance of elements-doped scaffolds follows a trend: 5Cu-BGC > 5Fe-BGC > 5Mn-BGC > 5Co-BGC > BGC. Compared to traditional nano-sized photothermal agents, bioactive elements-induced functional scaffolds have better biosecurity and bioactivity. Furthermore, 5Fe-BGC and 5Mn-BGC scaffolds displayed excellent bone-forming activity by stimulating the osteogenic differentiation of bone-forming cells. The major significance of the study is that the elements-doped bioactive glass-ceramics (5Fe-BGC, 5Mn-BGC) have great potential to be used as bifunctional scaffolds for photothermal tumor therapy and bone regeneration, representing a smart strategy for the treatment of bone tumors by combining dual functional bioactive ions with tissue engineering scaffolds.

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The spatial and developmental expression of mouse Vwa8 (von Willebrand domain-containing protein 8)

Publication date: Available online 13 April 2018
Source:Gene Expression Patterns
Author(s): Brian S. Grewe, Janet E. Richmond, David E. Featherstone
The Drosophila gene c12.2 was isolated in a screen examining mRNA binding proteins. Drosophila c12.2 is the mouse Vwa8 homolog. Various genome-wide associated studies have linked human Vwa8 to both neurological and oncological pathologies, which include autism, bipolar disorder, comorbid migraine, and acute myeloid leukemia, however, the function and role of the VWA8 protein remain poorly understood. To further analyze the Vwa8 gene in mouse, gene structure, protein homology modeling, and gene expression patterns were examined throughout mouse development. Our analyses indicate that the mouse Vwa8 gene produces two transcripts; the full-length Vwa8a is highly expressed relative to the truncated Vwa8b transcript across all developmental time points and tissues analyzed. Protein homology modeling indicates that VWA8a belongs to a novel protein superfamily containing both the midasin and cytoplasmic dynein 1 heavy chain 1 proteins. These data establish the development timeline and expression profile for both Vwa8a and Vwa8b, paving the way for future studies to determine the cellular role(s) of this highly conserved protein family.



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An epi(c)genetic war: Pathogens, cancer and human genome

Publication date: Available online 13 April 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Deepa Rajagopalan, Sudhakar Jha
Cancer is characterized by inter and intra-heterogeneity and this is also observed in the context of cancers caused by pathogens. Nearly 20% of all cancers are attributable to pathogenic organisms. Pathogenic infections result in deregulation of gene expression both by genetic and epigenetic mechanisms, thereby causing malignant transformation. Another characteristic of pathogen-induced cancers is the occurrence of chronic inflammation due to activation of the innate and adaptive arms of the immune system. This review focuses on the epigenetic changes induced by oncoviruses, parasites, cancer-causing bacteria and 'endogenous pathogens' to trigger host cell proliferation indefinitely as well as the inflammation associated with pathogen-induced cancers. The opportunity of targeting components of both pathogen and host epigenetic machinery to limit tumor progression is also discussed.



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Nervous system and primary liver cancer

Publication date: Available online 13 April 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Seogsong Jeong, Bo Zheng, Hongyang Wang, Qiang Xia, Lei Chen
Recent advances have found irregular activities of the nervous system-associated factors in the development and progression of primary liver cancer. These factors contributed in the regulation of migration, proliferation, and apoptosis of cancer cells, and took a role in modulating invasion, metastasis, and recurrence after curative treatment. In clinical researches, neural-related factors were found to be significant prognostic factors, suggesting that the interactions between nervous system and primary liver cancer are indispensable in understanding underlying biological mechanisms. Herein, we reviewed up-to-date achievements in this area and the future perspectives of the interactions between the nervous system and primary liver cancer.

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Protein restriction and cancer

Publication date: April 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1869, Issue 2
Author(s): Jie Yin, Wenkai Ren, Xingguo Huang, Tiejun Li, Yulong Yin
Protein restriction without malnutrition is currently an effective nutritional intervention known to prevent diseases and promote health span from yeast to human. Recently, low protein diets are reported to be associated with lowered cancer incidence and mortality risk of cancers in human. In murine models, protein restriction inhibits tumor growth via mTOR signaling pathway. IGF-1, amino acid metabolic programing, FGF21, and autophagy may also serve as potential mechanisms of protein restriction mediated cancer prevention. Together, dietary intervention aimed at reducing protein intake can be beneficial and has the potential to be widely adopted and effective in preventing and treating cancers.



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