Well-Defined Star-Shaped Polyglutamates with Improved Pharmacokinetic Profiles As Excellent Candidates for Biomedical Applications

Abstract

There is a need to develop new and innovative polymer carriers to be used as drug delivery systems and/or imaging agents owing to the fact that there is no universal polymeric system that can be used in the treatment of all diseases. Additionally, limitations with existing systems, such as a lack of biodegradability and biocompatibility, inevitably lead to side effects and poor patient compliance. New polymer therapeutics based on amino acids are excellent candidates for drug delivery, as they do not suffer from these limitations. This article reports on a simple yet powerful methodology for the synthesis of 3-arm star-shaped polyglutamic acid with well-defined structures, precise molecular weights (MW), and low polydispersity (Đ = <1.3). These were synthesized by ring-opening polymerization (ROP) of N-carboxyanhydrides (NCA) in a divergent method from novel multifunctional initiators. Herein, their exhaustive physicochemical characterization is presented. Furthermore, preliminary in vitro evaluation in selected cell models, and exhaustive in vivo biodistribution and pharmacokinetics, highlighted the advantages of these branched systems when compared with their linear counterparts in terms of cell uptake enhancement and prolonged plasma half-life.

In Vivo Imaging of MMP‐13 Activity Using a Specific Polymer‐FRET Peptide Conjugate Detects Early Osteoarthritis and Inhibitor Efficacy

“…To improve biodistribution of P‐ 18 and the quantity delivered to the articular joints, we considered conjugation to a biodegradable polymer carrier. We chose a PGA polymer of 30 kDa, as it represents an excellent candidate for the delivery of drugs and imaging probes, and we first investigated its suitability by monitoring the tissue distribution of PGA‐Cy5.5 . Our initial administration of PGA‐Cy5.5 to mice showed higher levels of fluorescence compared than those with Cy5.5 alone in various organs including knee joints (Figure C).…”

Polypeptide‐Based Conjugates as Therapeutics: Opportunities and Challenges

“…Additionally, ROP of NCAs renders polypeptides with conserved N‐terminal ends and can be used to introduce functionalities at the C‐terminal site for latter conjugation strategies. Synthetic aspects of polypeptide production are outside of the scope of this review and can be found elsewhere …”

“…Since then, a plethora of polymers have found use as drug delivery systems, including polymers of different origin (synthetic, semisynthetic, or natural), electrostatic nature, topology (linear, branched, star, dendrimeric etc. ), morphology, and degradability . The use of polymeric compounds as drug delivery systems confers unique properties to the active agent, including modified pharmacokinetics, controlled biodistribution, and/or sustained release.…”

Synthesis and Characterization of Stimuli‐Responsive Star‐Like Polypept(o)ides: Introducing Biodegradable PeptoStars

“…The branched architectures of these polymers consist of at least three linear arms linked to a central core, and thus the resulting 3D globular structure offers unique chemical and physical properties, namely smaller hydrodynamic radii, decreased solution viscosities, high end‐group functionalities, and encapsulation capabilities . Star‐like polymers that have been reported in literature are mainly based on polyethers, polyesters, polyacrylates, polyacrylamides, polyolefines, polypeptoids, or polypeptides . Interestingly, so far, star‐like polypept(o)ides have not been reported in literature, although this class may possess enormous potential for biomedical applications .…”