Targeting the Blood-brain Barrier with a Non-canonical Iron-mimicry Mechanism

Treatment of central nervous system (CNS) diseases is limited by the blood-brain barrier (BBB), a selective vascular interface restricting passage of most molecules from blood into brain. Specific transport systems have evolved allowing circulating polar molecules to cross the BBB and gain access to the brain parenchyma. However, to date, few ligands exploiting such systems have proven clinically viable in the setting of CNS diseases. We reasoned that combinatorial phage-display screenings in vivo would yield peptides capable of crossing the BBB and allow for the development of ligand-directed targeting strategies of the brain. Here we show the identification of a peptide mediating systemic targeting to the normal brain and to an orthotopic human glioma model. We demonstrate that this peptide functionally mimics iron through an allosteric mechanism and that a non-canonical association of (i) transferrin, (ii) the iron-mimic ligand motif, and (iii) transferrin receptor mediates binding and transport of particles across the BBB. We also show that in orthotopic human glioma xenografts, a combination of transferrin receptor over-expression plus extended vascular permeability and ligand retention result in remarkable brain tumor targeting. Moreover, such tumor targeting attributes enables Herpes simplex virus thymidine kinase-mediated gene therapy of intracranial tumors for molecular genetic imaging and suicide gene delivery with ganciclovir. Finally, we expand our data by analyzing a large panel of primary CNS tumors through comprehensive tissue microarrays. Together, our approach and results provide a translational avenue for the detection and treatment of brain tumors.

Editorial: What's Good for Families?

In the midst of the debates in Washington, D.C. over the budget, health care, welfare, and foreign affairs, a central question remains unanswered ~ what is good for families? Part of the ongoing debate has included family preservation which has been both tauted as the solution for society's ills and, simultaneously, as the cause. The reality, of course, is somewhere in between. Family preservation is a new and exciting approach for helping the most basic unit of our society, families, do their job. The principles which guide family preservation grow out of professional helping values and practice experience. Family preservation is a powerful approach to practice which puts the families we are trying to help at the center of the process, not as "symptom bearers" or "dysfunctional systems," but as full partners. While family preservationists enter a family with their eyes wide open to help solve problems, sometimes very serious ones, most of their energy goes to finding strengths and resources in the family in order to meet its needs. It works! And thousands of families who have been helped, along with researchers and other practitioners, sing its praises.

Protect Children From Household Food Insecurity: Promote Access To Food and Stress-Alleviating Resources

Household food insecurity is associated with threats to children’s intellectual, behavioral, and psycho-emotional development. In addition to poor food quality and quantity, the stress associated with food insecurity can undermine caregiver mental health and family functioning. Evidence demonstrates that national assistance programs and policies are needed to ensure that families and children have access to adequate sources of healthy food and to stress-alleviating resources.