Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

Micromanaging cardiac regeneration:Targeted delivery of micro RNAs for cardiac repair and regeneration

The loss of cardiomyocytes during injury and disease can result in heart failure and sudden death, while the adult heart has a limited capacity for endogenous regeneration and repair. Current stem cell-based regenerative medicine approaches modestly improve cardiomyocyte survival, but offer neglectable cardiomyogenesis. This has prompted the need for methodological developments that crease de novo cardiomyocytes. Current insights in cardiac development on the processes and regulatory mechanisms in embryonic cardiomyocyte differentiation provide a basis to therapeutically induce these pathways to generate new cardiomyocytes. Here, we discuss the current knowledge on embryonic cardiomyocyte differentiation and the implementation of this knowledge in state-ofthe-art protocols to the direct reprogramming of cardiac fibroblasts into de novo cardiomyocytes in vitro and in vivo with an emphasis on micro RNA-mediated reprogramming. Additionally, we discuss current advances on state-of-theart targeted drug delivery systems that can be employed to deliver these micro RNAs to the damaged cardiac tissue. Together, the advances in our understanding of cardiac development, recent advances in micro RNAbased therapeutics, and innovative drug delivery systems, highlight exciting opportunities for effective therapies for myocardial infarction and heart failure.

Survival of encapsulated islets: More than a membrane story

At present, proven clinical treatments but no cures are available for diabetes, a global epidemic with a huge economic burden. Transplantation of islets ofLangerhans by their infusion into vascularized organs is an experimental clinical protocol, the first approach to attain cure. However, it is associated with lifelong use of immunosuppressants. To overcome the need for immunosuppression, islets are encapsulated and separated from the host immune system by a permselective membrane. The lead material for this application is alginate which was tested in many animal models and a few clinical trials. This review discusses all aspects related to the function of transplanted encapsulated islets such as the basic requirements from a permselective membrane(e.g., allowable hydrodynamic radii, implications of the thickness of the membrane and relative electrical charge). Another aspect involves adequate oxygen supply, which is essential for survival/performance of transplanted islets, especially when using large retrievable macrocapsules implanted in poorly oxygenated sites like the subcutis. Notably, islets can survive under low oxygen tension and are physiologically active at > 40 Torr. Surprisingly, when densely crowded, islets are fully functional under hyperoxic pressure of up to 500 Torr(> 300% of atmospheric oxygen tension). The review also addresses an additional category of requirements for optimal performance of transplanted islets, named auxiliary technologies. These include control of inflammation, apoptosis, angiogenesis, and the intra-capsular environment. The review highlights that curing diabetes with a functional bio-artificial pancreas requires optimizing all of these aspects, and that significant advances have already been made in many of them.

Complement activation and long-term graft function in ABO-incompatible kidney transplantation

BACKGROUND ABO-incompatible and ABO-compatible kidney transplantation are equivalent in terms of short-term graft and patient survival. This is thought to be the result of ABO-incompatible graft accommodation, which occurs when anti-blood group antibodies re-occur after transplantation but somehow do not yield their detrimental effect. The underlying mechanism is unclear, but one of the hypotheses is that this is the result of complement inhibition. Since virtually all ABO-incompatible graft biopsies are C4d positive, this complement inhibition must occur somewhere in the complement cascade after the formation of C4d has already taken place, but where exactly is unclear. It is also unclear whether complement inhibition is complete. Incomplete accommodation could explain why recent studies have shown that long-term graft function in ABOincompatible transplantation is somewhat inferior to ABO-compatible kidney transplantation.AIM To unravel the relationship between pre-transplant anti-ABO antibodies,complement activation, and long-term graft function.METHODS We included all 27 ABO-incompatible transplantations that were performed between 2008 and 2013 at the Academic Medical Center Amsterdam and the University Medical Center Groningen. For each ABO-incompatible transplantation, we included four ABO-compatible controls matched by age, sex,and transplantation date.RESULTS Graft and patient survival were not significantly different. The slope of kidney function during five-year follow-up was also not significantly different, but ABOincompatible recipients did have a lower kidney function at three months(creatinine clearance 58 vs 69 mL/min, P = 0.02, Modification of Diet in Renal Disease 46 vs 52 mL/min/1.73 m^2, P = 0.08), due to a high rate of early rejection(33% vs 15%, P = 0.03), mostly T-cell mediated. Pre-transplant anti-ABO Ig G titers were positively correlated with C5b-9 staining, which itself was positively correlated with the occurrence of T-cell mediated rejection. This may be the result of concurrent C5a formation, which could function as a costimulatory signal for T-cell activation.CONCLUSION Co-stimulation of T-cell activation by ongoing complement activation by antiABO antibodies may be responsible for an impaired long-term graft function in ABO-incompatible kidney transplantation.

Timely renal replacement therapy linked to better outcome in patients with sepsis-associated acute kidney injury

Background:Recent studies suggest that acute kidney injury(AKI)can be treated with renal replacement therapy(RRT).However,its benefits to patients with sepsis-associated AKI(SA-AKI),which is linked to high mortality and morbidity rates,remain under debate.The aim of this study was to compare the outcomes of different RRT strategies for patients with SA-AKI.Methods:This retrospective study evaluated patients who were admitted to the hospital with sepsis and devel-oped SA-AKI during hospitalization from 1st January 2014 to 31st January 2019.Mortality,renal recovery,and systemic organ function at 90 days following admission were compared between the RRT group(RG)and non-RRT group(NRG),as well as the early-RRT group(EG)and delayed-RRT group(DG).The groups were defined according to the time from admission to RRT initiation(criterion 1,EG1 and DG1)and Kidney Disease Improving Global Outcomes(KDIGO)classification(criterion 2,EG2 and DG2).Categorical and continuous variables were compared using the chi-squared test or Fisher’s exact test and Student’s t-test or Wilcoxon test.Kaplan-Meier curves were constructed to determine the unadjusted survival rates for the different subgroups.Results:A total of 116 patients were included in this study;of those,38 received RRT and 46 expired within 90 days.Among different strategies of RRT,there were no significant differences found in 90-day mortality(RG vs.NRG:𝜒2=0.610,P=0.435;EG1 vs.DG1:𝜒2=0.835,P=0.360;EG2 vs.DG2:𝜒2=0.022,P=0.899)and renal recovery.However,the values of change in sequential organ failure assessment(ΔSOFA)max-min of patients in the EG and RG were significantly higher than those recorded in the NRG(ΔSOFA RG=7.0,ΔSOFA NRG=3.60,ΔSOFA EG1=9.00,ΔSOFA EG2=6.30;P<0.050).Also,the 90-day renal recovery in the EG was better than that noted in the DG with criterion 1(87.5%vs.38.5%,respectively,𝜒2=10.425,P=0.032),suggesting that RRT(especially timely RRT)may be beneficial to the restoration of systemic organ function in patients with SA-AKI.Conclusion:RRT did not reduce the 90-day mortality among patients with SA-AKI.However,timely RRT may benefit the restoration of systemic organ function,thereby improving the quality of life of patients.