A Novel Thermal-driven Self-assembly Method to Prepare Albumin Nanoparticles: Formation Kinetics, Degradation Behavior and Formation Mechanism.

Nanoparticles based on bovine serum albumin (BSA), which shares 76% homology with human serum albumin (HSA), have emerged as a promising candidate for the efficient delivery of anticancer drugs. Thermal-driven self-assembly is a novel organic solvent-free approach to produce albumin nanoparticles. In our previous study, some features of this nanoparticle such as drug loading efficiency, drug encapsulation efficiency and drug release kinetics have been evaluated. However, the formation mechanism that determines the above nanoparticle properties remains unclear. Here, we investigated the formation kinetics and mechanism using spectroscopic methods including fluorescence spectroscopy, circular dichroism (CD) and differential scanning calorimetry (DSC). We also applied chemical analysis methods that measured the content changes of albumin active groups and vanillin. To verify the covalent networks in the nanoparticles, trypsin and glutathione (GSH) were used separately to cleave the peptide bonds and disulfide bridges, and dynamic light scattering (DLS) and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) were used to analyze the degraded samples. BSA nanoparticles started to form at 10 min and were completely formed at 120 min. With the digestion of trypsin, more than 50% of the nanoparticles were degraded within 60 min. CD spectra showed that α-helical structure of BSA decreased from 42.3% to 39.8% and 37.7% after heating for 10 and 60 min, respectively. In the DSC thermogram, the melting peak of BSA nanoparticles was 229.14℃, which is about 12℃ higher than the physical mixture of BSA and vanillin, indicating that chemical reactions occurred during the nanoparticle formation and formed a new more stable substance. Moreover, the results of active group assay, GSH degradation and SDS-PAGE experiments also proved that disulfide bonds and peptide bonds were formed between BSA molecules, whereas Schiff bases were formed between BSA and vanillin molecules. Formation kinetics and degradation behavior are important properties to characterize albumin nanoparticles and should be paid attention to. Not only that, this study also provides an effective way to study the formation mechanism of protein-based nanodrug delivery systems.

Recent Advances in Enhancement of Dissolution and Supersaturation of Poorly Water-Soluble Drug in Amorphous Pharmaceutical Solids: A Review.

Amorphization is one of the most effective pharmaceutical approaches to enhance the dissolution and oral bioavailability of poorly water-soluble drugs. In recent years, amorphous formulations have been experiencing rapid development both in theoretical and practical application. Based on using different types of stabilizing agents, amorphous formulations can be mainly classified as polymer-based amorphous solid dispersion, coamorphous formulation, mesoporous silica-based amorphous formulation, etc. This paper summarizes recent advances in the dissolution and supersaturation of these amorphous formulations. Moreover, we also highlight the roles of stabilizing agents such as polymers, low molecular weight co-formers, and mesoporous silica. Maintaining supersaturation in solution is a key factor for the enhancement of dissolution profile and oral bioavailability, and thus, the strategies and challenges for maintaining supersaturation are also discussed. With an in-depth understanding of the inherent mechanisms of dissolution behaviors, the design of amorphous pharmaceutical formulations will become more scientific and reasonable, leading to vigorous development of commercial amorphous drug products.

Combinatory therapy of MRP1-targeted photoimmunotherapy and liposomal doxorubicin promotes the antitumor effect for chemoresistant small cell lung cancer.

Small cell lung cancer (SCLC), considered a mortal recalcitrant cancer, is a severe healthcare issue because of its poor prognosis, early metastasis, drug resistance and limited clinical treatment options. In our previous study, we established a MRP1-targeted antibody-IR700 system (Mab-IR700) for near infrared photoimmunotherapy (NIR-PIT) which exhibited a promising therapeutic effect on drug resistant H69AR cells both in vitro and in vivo, though the tumor growth suppression effect did not last long with a single round of PIT treatment. To achieve a better anticancer effect, we have combined Mab-IR700-mediated NIR-PIT with liposomal doxorubicin (Doxil®) and investigated the in vitro and in vivo cytotoxicity by using a H69AR/3T3 cell co-culture model in which 3T3 cells were used to mimic stromal cells. Cytotoxicity experiments demonstrated the specificity of Mab-IR700 to H69AR cells, while cytotoxicity and flow cytometry experiments confirmed that H69AR cells were doxorubicin-resistant. Compared with Mab-IR700-mediated PIT or Doxil-mediated chemotherapy, the combination therapy exhibited the best cell killing effect in vitro and superior tumor growth inhibition and survival prolongation effect in vivo. Super enhanced permeability and retention (SUPR) effect was observed in both co-culture spheroids and tumor-bearing mice. Owing to an approximately 9-fold greater accumulation of Doxil within the tumors, NIR-PIT combined with Doxil resulted in enhanced antitumor effects compared to NIR-PIT alone. This photoimmunochemotherapy is a practical strategy for the treatment of chemoresistant SCLC and should be further investigated for clinical translation.

Recent Developments of Flavonoids with Various Activities.

Flavonoids, a series of compounds with a C6-C3-C6 structure, mostly originate from plant metabolism. Flavonoids have shown beneficial effects on many aspects of human physiology and health. Recently, many flavonoids with various activities have been discovered, which has led to more and more studies focusing on their physiological and pharmacodynamic activities. The anticancer and anti-viral activities especially have gained the attention of many researchers. Therefore, the discovery and development of flavonoids as anti-disease drugs has great potential and may make a significant contribution to fighting diseases. This review focus on the discovery and development of flavonoids in medicinal chemistry in recent years.

Delivery of an ectonucleotidase inhibitor with ROS-responsive nanoparticles overcomes adenosine-mediated cancer immunosuppression.

Tumor evasion of immune destruction is associated with the production of immunosuppressive adenosine in the tumor microenvironment (TME). Anticancer therapies can trigger adenosine triphosphate (ATP) release from tumor cells, causing rapid formation of adenosine by the ectonucleotidases CD39 and CD73, thereafter exacerbating immunosuppression in the TME. The goal of this study was to develop an approach to facilitate cancer therapy-induced immunogenic cell death including ATP release and to limit ATP degradation into adenosine, in order to achieve durable antitumor immune response. Our approach was to construct reactive oxygen species (ROS)-producing nanoparticles that carry an ectonucleotidase inhibitor ARL67156 by electronic interaction and phenylboronic ester. Upon near-infrared irradiation, nanoparticle-produced ROS induced ATP release from MOC1 cancer cells in vitro and triggered the cleavage of phenylboronic ester, facilitating the release of ARL67156 from the nanoparticles. ARL67156 prevented conversion of ATP to adenosine and enhanced anticancer immunity in an MOC1-based coculture model. We tested this approach in mouse tumor models. Nanoparticle-based ROS-responsive drug delivery reprogramed the immunogenic landscape in tumors, eliciting tumor-specific T cell responses and tumor regression, conferring long-term survival in mouse models. We demonstrated that TME reprograming sets the stage for response to anti-programmed cell death protein 1 (PD1) immunotherapy, and the combination resulted in tumor regression in a 4T1 breast cancer mouse model that was resistant to PD1 blockade. Furthermore, our approach also induced immunological effects in patient-derived organotypic tumor spheroid model, suggesting potential translation of our nanoparticle approach for treating human cancers.

MRP1-targeted near infrared photoimmunotherapy for drug resistant small cell lung cancer.

Small cell lung cancer (SCLC), one of the most aggressive cancers, has a high mortality rate and poor prognosis, and the clinical therapeutic outcomes of multidrug resistant SCLC are even worse. Multidrug resistance protein 1 (MRP1), one of the ATP-binding cassette (ABC) transporter proteins that cause decreased drug accumulation in cancer cells, is overexpressed in drug resistant SCLC cells and could be a promising target for treating the patients suffering from this illness. Near infrared photoimmunotherapy (NIR-PIT) is a newly developed approach for targeted cancer treatment which uses a conjugate of a monoclonal antibody and photoabosorber IR700 followed by NIR light irradiation to induce rapid cancer cell death. In the present study, an anti-MRP1 antibody (Mab) -IR700 conjugate (Mab-IR700) was synthesized, purified and used to treat chemoresistant SCLC H69AR cells that overexpressed MRP1, while non-MRP1-expressing H69 cells were used as a control. Then, the photokilling and tumor suppression effect were separately evaluated in H69AR cells both in vitro and in vivo. Higher cellular delivery of Mab-IR700 was detected in H69AR cells, whereas there was little uptake of IgG-IR700 in both H69 and H69AR cells. Due to the targeting activity of Mab, stronger photokilling effect was found both in H69AR cells and spheroids treated with Mab-IR700, while superior tumor suppression effect was also observed in the mice treated with Mab-IR700 and light illumination. Photoacoustic imaging results proved that oxygen was involved in NIR-PIT treatment, and TUNEL staining images showed the occurrence of cell apoptosis, which was also testified by HE staining. This research provides MRP1 as a novel target for PIT and presents a prospective way for treating drug resistant SCLC and, thus, should be further studied.

Research Development, Optimization and Modifications of Anti-cancer Peptides.

Anti-cancer peptides play an important role in the area of cancer inhibition. A variety of anti- cancer peptides have emerged through the extraction and structural modification of peptides from biological tissues. This review provides the research background of anti-cancer peptides, the introduction of the mechanism of anti-cancer peptides for inhibition of cancers, the discovery and development along with optimization and modifications of these peptides in the clinical application. In conclusion, it can be said that anti-cancer peptides will play a major role in the future oncologic clinic.

Physical stability of amorphous pharmaceutical solids: Nucleation, crystal growth, phase separation and effects of the polymers.

Compared to their crystalline forms, amorphous pharmaceutical solids present marvelous potential and advantages for effectively improving the oral bioavailability of poorly water-soluble drugs. A central issue in developing amorphous pharmaceutical solids is the stability against crystallization, which is particularly important for maintaining their advantages in solubility and dissolution rate. This review provides a comprehensive overview of recent studies focusing on the physical stability of amorphous pharmaceutical solids affected by nucleation, crystal growth, phase separation and the addition of polymers. Moreover, we highlight the novel technologies and theories in the field of amorphous pharmaceutical solids. Meanwhile, the challenges and strategies in maintaining the physical stability of amorphous pharmaceutical solids are also discussed. With a better understanding of physical stability, the more robust amorphous pharmaceutical formulations with desired pharmaceutical performance would be easier to achieve.

The prognostic impact of tumour-associated macrophages and Reed-Sternberg cells in paediatric Hodgkin lymphoma.

BACKGROUND: Tumour-associated macrophages (TAM) are associated with treatment failure in adults with Hodgkin lymphoma (HL). Equivalent data in paediatric HL are sparse. We aimed to determine the prognostic significance of TAM and Reed-Sternberg (RS) cells in paediatric HL. METHODS: All children aged 0-18 with HL between 1980 and 2009 with available diagnostic biopsy material were identified. A treatment failure-enriched cohort was assembled. Demographic, disease and outcome data were abstracted. Tissue microarrays with duplicate cores were constructed from diagnostic biopsy material and stained with immunohistochemical markers for TAM (CD68, CD163) and RS (CD30). A high score was defined as >5% positive cells relative to overall cellularity in any core. The association of candidate variables with event-free survival (EFS) was determined using Cox proportional hazards. RESULTS: The final study cohort comprised 96 patients with a median age of 14 years (interquartile range 11-15). Agreement on scores between cores from the same biopsy revealed weighted kappas of 0.60, 0.68 and 0.73 for CD30, CD68 and CD163 respectively, indicating moderate tumour heterogeneity. In univariate analysis, a high CD30 score was significantly associated with treatment failure (hazard ratio (HR) 2.27; 95th confidence interval 1.01-5.11; p<0.05). High CD68 and CD163 scores were not associated with EFS. CONCLUSIONS: Unlike adult HL, a higher percentage of RS cells was associated with poor outcome, while a higher percentage of TAM was not. Adult HL findings may not extend to paediatric HL. Cooperative group trials of paediatric HL should prospectively determine the association of different components of the tumour microenvironment with outcome.

The magnitude and predictors of abandonment of therapy in paediatric acute leukaemia in middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Abandonment of therapy is a significant cause of paediatric cancer treatment failure in low- to middle-income countries (LMIC), but its impact has been underestimated. We performed a meta-analysis to determine the magnitude of abandonment in paediatric leukaemia in LMIC and sought to identify patient-, centre- and country-specific predictors of abandonment. PATIENTS AND METHODS: We searched seven databases to identify paediatric oncology cohorts followed up from diagnosis and treated in LMIC. All languages were included. Two reviewers independently selected articles and extracted data. Authors were contacted for additional information. Subgroup analyses were planned a priori. RESULTS: Of 22,384 publications, 318 in eight languages met criteria for full text review. 157 studies met analysis inclusion criteria. Abandonment rates (ARs), obtained for 83 of the 157 studies (52.9%), ranged from 0% to 74.5%. ARs were frequently unreported and available only directly from authors. Forty studies (10,494 children in 20 countries) were quantitatively analysed. ARs for acute lymphoblastic laeukemia in lower-middle-income countries (lower-MICs) were higher than in upper-middle-income countries (29%, 95% confidence interval (CI) 23-36% versus 2%, 95% CI 1-3%; p<0.0001) but were heterogeneous (I(2)=98%; p<0.0001). This heterogeneity was not explained by centre-specific (free versus paid treatment) or country-specific (government health expenditure, per-capital income) subgroups. CONCLUSIONS: In LMICs, ARs are highest in lower-MICs. However, their broad range suggests that low ARs are possible in resource-constrained settings. Analysis of outliers may suggest interventions for use at other centres. Methodologically appropriate reporting of ARs should be adopted. Future research should evaluate interventions targeting abandonment.