Systemically Administered, Target-Specific Therapeutic Recombinant Proteins and Nanoparticles for Regenerative Medicine

Abstract

Growth factors, chemokines, and cytokines responsible for tissue regeneration have been identified. Their therapeutic usage in humans is almost nonexistent because of the difficulty in maintaining their bioactivity in the proteaserich milieu of injured tissues. Safety concerns have ruled out the systemic administration of growth factors. Angiogenic vasculature forming in the regenerating tissues has unique molecular structures, so-called "zip/postal codes". These unique vascular zip codes provide an opportunity for target-specific delivery of systemically administered therapeutics to tissue injuries by ligands (using peptides or antibodies as a delivery vehicle) binding to these specific structures. Molecules with therapeutic potential can also be packaged into nanocarriers which then can be targeted to the desired location by placing large number of peptides on the nanoparticle. The targeted delivery of systemically administered recombinant proteins to the injured tissue is hopefully rapidly advanced to provide new therapeutics to regenerative medicine.

Generation of a multi‐functional, target organ‐specific, anti‐fibrotic molecule by molecular engineering of the extracellular matrix protein, decorin

“…One of the goals of modern pharmaceutical treatment is to be as target specific as possible; drugs should be highly active against the disease while having as few side effects in the healthy parts of the body as possible (Järvinen et al, ). This goal is usually obtained by developing drugs that act on molecules selectively expressed in the diseased organ.…”

“…Injured tissue provides an excellent target for ligand‐mediated delivery of systemically administered therapeutic agents (Järvinen et al, ). The first actual sign of tissue regeneration after the injury and subsequent inflammatory period is massive angiogenesis in the injured area.…”

“…The first actual sign of tissue regeneration after the injury and subsequent inflammatory period is massive angiogenesis in the injured area. The formation of angiogenic capillaries is induced by the hypoxia resulting from disrupted circulation in the damaged tissue (Barker et al, ; Järvinen et al, ). Hypoxia triggers the production of angiogenic growth factors, which induce angiogenesis in the injured tissue.…”

“…Expressing a short homing peptide as part of a larger recombinant fusion protein makes it possible to circumvent two major pharmacological disadvantages of peptides, short half‐life in the circulation and low binding affinity towards the target molecule (Järvinen et al, ). Thus, multiple therapeutic multi‐functional recombinant fusion proteins consisting of vascular targeting element and a therapeutic molecule have been described in the biomedical literature, and the most advanced ones have already moved to clinical trials (Phase III) in humans.…”

“…For example, they are shorter that the complementary determining regions inserted into therapeutic antibodies, which usually do not cause immune reaction and are considered safe as drugs. Furthermore, vascular homing peptides sometimes share sequence homology with parts of human and mammalian proteins, as is the case with CAR peptide, which is also likely to reduce immunogenicity (Järvinen et al, ).…”