Synthesis and In Vivo Pharmacokinetic Evaluation of Degradable Shell Cross-Linked Polymer Nanoparticles with Poly(carboxybetaine) versus Poly(ethylene glycol) Surface-Grafted Coatings

Abstract

Nanoparticles with tunable pharmacokinetics are desirable for various biomedical applications. Poly(ethylene glycol) (PEG) is well known to create “stealth” effects to stabilize and extend the blood circulation of nanoparticles. In this work, poly(carboxybetaine) (PCB), a new non-fouling polymer material, was incorporated as surface-grafted coatings, conjugated onto degradable shell crosslinked knedel-like nanoparticles (dSCKs) composed of poly(acrylic acid)- based shells and poly(lactic acid) (PLA) cores, to compare the in vivo pharmacokinetics to their PEG-functionalized analogs. A series of five dSCKs was prepared from amphiphilic block copolymers, having different numbers and lengths of either PEG or PCB grafts, by supramolecular assembly in water followed by shell crosslinking, and then studied by a lactate assay to confirm their core hydrolytic degradabilities. Each dSCK was also conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) macrocyclic chelators and tyramine moieties to provide for 64Cu and/or radiohalogen labeling. The high specific activity of 64Cu radiolabeling ensured nanogram administration of dSCKs for in vivo evaluation of their pharmacokinetics. Biodistribution studies demonstrated comparable in vivo pharmacokinetic profiles of PCB-grafted dSCKs to their PEG-conjugated counterparts. These results indicated that PCB-functionalized dSCKs have great potential as a theranostic platform for translational research.

Recent advances of zwitterionic carboxybetaine materials and their derivatives

“…pCBs have drawn special interests for their advantages over other zwitterionic materials, including versatile structural options, [8,9] simple synthetic approaches, [16] capability of further functionalization, [8,[17][18][19] ultra-low protein fouling and biofouling levels, [20,21] as well as good biocompatibility. [22][23][24][25] Zwitterionic pCB materials have many derivatives (Figure 1). Their properties and functions can be adjusted at the monomer level.…”

Nanocarriers with tunable surface properties to unblock bottlenecks in systemic drug and gene delivery

“…Zwitterionic nanocarriers based on carboxybetaine acrylate also significantly resisted the nonspecific adsorption of serum proteins [68]. Biodistribution studies demonstrated that zwitterionic poly(carboxybetaine) surface-grafted nanoparticles had comparable in vivo pharmacokinetic profiles to their PEG-conjugated counterparts [69]. The excellent anti-fouling properties of zwitterionic nanocarriers make a promising alternative to conventional PEG coating for "stealthy" formulations [70].…”

Effect of Synthetic Polymers on tRNA Nanoparticle Formation

“…Synthetic polymers play a major role in therapeutic drug, protein and gene delivery systems [1][2][3][4][5][6]. Among synthetic polymers (Scheme 1), poly (ethylene glycol) and its derivatives show potential applications in gene and drug delivery due to their solubility, nontoxicity and biocompatibility [1][2][3].…”

“…Among synthetic polymers (Scheme 1), poly (ethylene glycol) and its derivatives show potential applications in gene and drug delivery due to their solubility, nontoxicity and biocompatibility [1][2][3]. Dendrimers (Scheme 1) are also unique synthetic macromolecules of nanometer dimensions with a highly branched structure and globular shape with strong affinity towards DNA and RNA complexation [4][5][6][7][8][9][10]. It has been shown that synthetic polymers induce significant changes in DNA and RNA solubility and structure under given conditions [8][9][10][11][12][13][14][15][16][17][18][19][20].…”