The impact of protein therapeutics in healthcare is steadily increasing, due to advancements in the field of biotechnology and a deeper understanding of several pathologies. However, their safety and efficacy are often limited by instability, short half-life and immunogenicity. Nanodelivery systems are currently being investigated for overcoming these limitations and include covalent attachment of biocompatible polymers (PEG and other synthetic or naturally derived macromolecules) as well as protein nanoencapsulation in colloidal systems (liposomes and other lipid or polymeric nanocarriers). Such strategies have the potential to develop next-generation protein therapeutics. Herein, we review recent research progresses on these nanodelivery approaches, as well as future directions and challenges.
In this study, we
compare poly(glycerol monomethacrylate) (PGMA)
of different chain lengths and architectures (linear and two-arm)
with poly(poly(ethylene glycol) methyl ether methacrylate) (PPEGMA)
as an alternative polymer platform for the synthesis of a new generation
of protein–polymer conjugates. Mono- and two-arm functional
atom-transfer radical polymerization (ATRP) initiators were designed
and selectively attached to lysozyme at the N-terminus via reductive
amination. Site-specific, grafting from activator regenerated by electron
transfer (ARGET) ATRP was carried out in phosphate buffer, and the
reaction parameters were optimized to obtain polymer conjugates with
predetermined molar mass and topology. The activity preservation under
proteolytic and high-temperature conditions showed a clear dependence
on the structure of the repeating unit and on the macromolecular architecture.
These results highlighted the potential of PGMA as a poly(ethylene
glycol) (PEG) alternative for the half-life extension of biotherapeutics.
Moreover, this synthetic approach may inspire the design of a new
class of protein–polymer conjugates through an optimal combination
of macromolecular composition and topology.
This review aims to highlight the importance of particle shape in the design of polymeric nanocarriers for drug delivery systems, along with their size, surface chemistry, density, and rigidity. Current manufacturing methods used to obtain non-spherical polymeric nanocarriers such as filomicelles or nanoworms, nanorods and nanodisks, are firstly described. Then, their interactions with biological barriers are presented, including how shape affects nanoparticle clearance, their biodistribution and targeting. Finally, their drug delivery properties and their therapeutic efficacy, both in vitro and in vivo, are discussed and compared with the characteristics of their spherical counterparts.
Doxorubicin (DOX)-loaded polymer nanoparticles based on poly(ethylene glycol)-poly(ε-caprolactone) copolymers with a complex macromolecular topology are proposed to tackle the matrix metalloproteinase (MMP)-rich tumor environment. Linear, 4-arm comb-like copolymers and 4-arm brush block copolymers were synthesized through a combination of ring opening polymerization and atom transfer radical polymerization, in order to control the molar mass distribution, the arm/brush architecture, as well as the final size and DOX loading of self-assembled nanoparticles obtained by nanoprecipitation. The optimized nanocarriers were conjugated with penetrating low molecular weight protamine peptides coupled to a polyanionic inhibitory domain cleavable by matrix metalloproteinase-2 (MMP2). DOX-loaded, MMP2-activable nanocarriers were evaluated in the context of glioblastoma (GBM), a brain tumor characterized by remarkable and relevant MMP2 expression. Uptake and cytotoxicity in patient-derived GBM cells correlated with the level of MMP2 enzymatic activity in a dose-and time-dependent manner. No effects were observed in nontumoral endothelial cells that do not express MMP2. Results demonstrated that, by tuning polymer topology and peptide sequence, nanoparticle self-assembly, DOX encapsulation, and delivery can be optimized for the development of an advanced treatment for MMP2-overexpressing tumors.
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