Combating bone marrow failure with polymer materials.

Bone marrow failure (BMF) has become one of the most studied autoimmune disorders, particularly due to its prevalence both as an inherited disease, but also as a result of chemotherapies. BMF is associated with severe symptoms such as bleeding episodes and susceptibility to infections, and often has underlying characteristics, such as anemia, thrombocytopenia, and neutropenia. The current treatment landscape for BMF requires stem cell transplantation or chemotherapies to induce immune suppression. However, there is limited donor cell availability or dose related toxicity associated with these treatments. Optimizing these treatments has become a necessity. Polymer-based materials have become increasingly popular, as current research efforts are focused on synthesizing novel cell matrices for stem cell expansion to solve limited donor cell availability, as well as applying polymer delivery vehicles to intracellularly deliver cargo that can aid in immunosuppression. Here, we discuss the importance and impact of polymer materials to enhance therapeutics in the context of BMF.

Alcohol-containing protein transduction domain mimics.

The application and design of protein transduction domains (PTDs) and protein transduction domain mimics (PTDMs) have revolutionized the field of biomacromolecule delivery. Our group has previously synthesized block copolymer PTDMs with well-defined hydrophobic and cationic blocks via ring-opening metathesis polymerization (ROMP). We have optimized the balance of hydrophobicity and cationic density to intracellularly deliver model proteins, active proteins, and antibodies. Despite the presence of serine, threonine, and tyrosine in naturally occurring PTDs, synthetic analogs have yet to be studied in PTDMs. In our present work, we introduce different alcohol groups to our PTDM structures as a new design parameter. A library of nine novel PTDMs were synthesized to incorporate alcohol groups of varying structures and evaluated based on their ability to intracellularly deliver fluorescently labeled antibodies. One PTDM in this novel library, named PTDM4, incorporates alcohol groups in both the hydrophobic and cationic blocks and was found to be the best performing PTDM with almost twice the median fluorescence intensity of the delivered antibody and half the cationic density compared to our positive control, a PTDM thoroughly studied by our group. PTDM4 was further studied by intracellularly delivering the active enzyme, TAT-Cre Recombinase. The activity of TAT-Cre Recombinase delivered by PTDM4 was comparable to that of the positive control, again with half the cationic density. This study is one of the first to examine the effects of alcohol groups on intracellular antibody and active enzyme delivery.

Functional antibody delivery: Advances in cellular manipulation.

The current therapeutic antibody market in the U.S. consists of 100 antibody-based products and their market value is expected to explode beyond $300 billion by 2025. These therapies are presently limited to extracellular targets due to the innate inability of antibodies to transverse membranes. To expand the number of accessible therapeutic targets, intracellular antibody delivery is necessary. Many delivery vehicles for antibodies have been used with some promising results, such as nanoparticles and cell penetrating polymers. Despite the success of these delivery platforms using model antibody cargo, there is a surprisingly small number of studies that focus on functional antibody delivery into the cytosol that also measures a cellular response. Antibodies can be designed for essentially unlimited targets, including proteins and DNA, that will ultimately control cell function once delivered inside cells. Advancement in cellular manipulation depends on the application of intracellularly delivering functional antibodies to achieve a desired result. This review focuses on the emerging field of functional antibody delivery which enables various cellular responses and cell manipulation.