The identification and production of recombinant morphogens and growth factors that play key roles in tissue regeneration have generated much enthusiasm and numerous clinical trials, but the results of many of these trials have been largely disappointing. Interestingly, the trials that have shown benefit all contain a common denominator, the presence of a material carrier, suggesting strongly that spatio-temporal control over the location and bioactivity of factors after introduction into the body is crucial to achieve tangible therapeutic effect. Sophisticated materials systems that regulate the biological presentation of growth factors represent an attractive new generation of therapeutic agents for the treatment of a wide variety of diseases. This review provides an overview of growth factor delivery in tissue engineering. Certain fundamental issues and design strategies relevant to the material carriers that are being actively pursued to address specific technical objectives are discussed. Recent progress highlights the importance of materials science and engineering in growth factor delivery approaches to regenerative medicine.

https://royalsocietypublishing.org/doi/pdf/10.1098/rsif.2010.0223

Growth factor delivery-based tissue engineering: general approaches and a review of recent developments

A method for targeting to and retaining intravenously injected nanoparticles at the site of acute myocardial infarction in a rat model is described. Enzyme-responsive peptide-polymer amphiphiles are assembled as spherical micellar nanoparticles, and undergo a morphological transition from spherical-shaped, discrete materials to network-like assemblies when acted upon by matrix metalloproteinases (MMP-2 and MMP-9), which are up-regulated in heart tissue post-myocardial infarction.

/pdf/enzyme-responsive-nanoparticles-for-targeted-accumulation-4cxdl4egvh.pdf

Enzyme-Responsive Nanoparticles for Targeted Accumulation and Prolonged Retention in Heart Tissue after Myocardial Infarction.

http://dadun.unav.edu/bitstream/10171/18289/3/Formiga%20et%20al-Manuscript-JCR-D-10-00464R1.pdf

Sustained release of VEGF through PLGA microparticles improves vasculogenesis and tissue remodeling in an acute myocardial ischemia-reperfusion model.

The surface of a cell represents a collection of macromolecules, which provides the cell with a unique cellular landscape specific to the type and state of the cell. Ligands that discriminate between subtle differences in cell surface phenotypes have utility in a wide variety of research and clinical applications. In particular, cell-binding ligands that can deliver biologically active cargo to a specific cell type or a diseased cell are highly sought. While the concept of the magic bullet drug was introduced by Paul Erlich over a century ago, the scientific community has yet to fully realize this goal.1 This stems primarily from hurdles in obtaining high-affinity cell-binding ligands with the necessary discriminating power. The difficulty of the problem is realized by considering that the human body contains 210 distinct cell types, not including diseased cells, and is composed of ~1014 cells. Furthermore, once isolated, the ligand must be able to be prepared in large quantities, must be amenable to chemical modification for optimal in vivo biodistribution, and must be able to be tailored to suit a variety of clinical applications.

As antibodies typically have high affinity and specificity for their targets, they have garnered attention as cell-targeting agents. Monoclonal antibodies (mAbs) can be generated against differentially expressed cell surface features, and the number of FDA-approved mAbs that bind to cell surface antigens continues to grow.2 mAb therapies are used to treat a variety of diseases. However, most of the clinically approved therapeutic mAbs are not conjugated to drugs or toxins and therefore fall into the category of molecularly targeted therapies. Such antibodies function passively by either blocking the activity of receptors or activating the immune system to destroy the antibody target.3 Only a few clinically approved mAbs carry a deliverable. For example, two radiolabeled antibodies, Zevalin (ibritumomab tiuxetan) and Bexxar (iodine-131 tositumomab), are approved in the United States; both are anti-CD20 antibodies used for select patients with non-Hodgkin’s lymphoma. The only clinically approved antibody–drug conjugate in the United States is Adcetris (brentuximab vedotin). Approved in 2011, Adcetris is an anti-CD30 antibody conjugated to the highly toxic microtubule-disrupting agent monomethyl auristatin E and is utilized for the treatment of Hodgkin’s lymphoma (HL) or systemic anaplastic large-cell lymphoma (sALCL). Mylotarg, a calicheamicin anti-CD33 antibody conjugate, was recently removed from the market after 10 years in the clinic for failing to show efficacy.

Despite their successes, mAbs have limitations, especially in their ability to serve as delivery vehicles. Significantly, chemically modifying antibodies is challenging, and production costs are substantial. Additionally, nonspecific clearance of antibodies by the reticuloendothelial system can lead to accumulation of conjugated drugs or toxins in unwanted sites such as the liver and bone, damaging these organs.4,5 Recently, concerns have risen over post-translational modifications on mAbs, especially glycosylation, which can trigger severe hypersensitivity reactions. Due to their long in vivo half-lives, intact mAbs are not well suited for molecular imaging techniques, requiring the use of antibody fragments (Fab’s). Of the approved mAb therapies, only 11 different cell surface biomarkers are targeted. This is a minute fraction of the cell surface repertoire.

Peptides are an attractive alternative to antibody-targeting therapies. Unlike antibodies, peptides are easy to synthesize in large quantities,6 and their smaller size improves tissue penetration while preventing nonspecific uptake by the reticuloendothelial system. Additionally, peptides can be chemically modified to alter affinity, charge, hydrophobicity, stability, and solubility and can be optimized for in vivo use through reiterative modifications. Importantly, peptides can display antibody-like affinities for their receptors. The biological half-life of peptides is well matched with that of many clinically used radionuclides, making them attractive probes for molecular imaging. Several naturally occurring peptides have been used as delivery agents. For example, reproductive hormone peptides and their derivatives are useful for tumor targeting, due to overexpression of their receptors on many cancer cells.7,8 However, relying on known peptidic ligands limits the types of cells that can be targeted. For this reason, chemists and biologists have turned to diverse peptide libraries to select additional peptides that bind to specific cell types.

Combinatorial Peptide Libraries: Mining for Cell-Binding Peptides

We report a nanoparticulate system capable of targeting the heart after myocardial infarction (MI). Targeting is based on overexpression of angiotensin II type 1 (AT1) receptor in the infarcted heart. Liposomes 142 nm in diameter were conjugated with a ligand specific to AT1. The nanoparticles were able to specifically target cardiac cells in vitro, and in the infarcted heart after intravenous injection in vivo. This system may be useful for delivering therapeutic agents specifically to the infarcted heart.

/pdf/nanoparticles-targeting-the-infarcted-heart-24m23m2r79.pdf

Nanoparticles targeting the infarcted heart.

Recent attempts at rebuilding the myocardium using stem cells have yielded disappointing results. The lack of a supporting vasculature may, in part, explain these disappointing findings. However, concerns over possible side effects have hampered attempts at revascularizing the infarcted myocardium using systemic delivery of proangiogenic compounds. In this study, we develop the technology to enhance the morphology and function of postinfarct neovasculature. Previously, we have shown that the up-regulated expression of endothelial cell adhesion molecules in the myocardial infarction (MI) region provides a potential avenue for selectively targeting drugs to infarcted tissue. After treatment with anti-P-selectin-conjugated liposomes containing vascular endothelial growth factor (VEGF), changes in cardiac function and vasculature post-MI were quantified in a rat MI model. Targeted delivery of VEGF to post-MI tissue resulted in significant increase in fractional shortening and improved systolic function. These functional improvements were accompanied by a 21% increase in the number of anatomical vessels and a 74% increase in the number of perfused vessels in the MI region of treated animals. No significant improvements in cardiac function were observed in untreated, systemic VEGF-treated, nontargeted liposome-treated, or blank immunoliposome-treated animals. Targeted delivery of low doses of proangiogenic compounds to post-MI tissue results in significant improvements in cardiac function and vascular structure.

Zhanna Ivanov

Papers

Targeting VEGF-encapsulated immunoliposomes to MI heart improves vascularity and cardiac function