Zwitterionic Nanocarrier Surface Chemistry Improves siRNA Tumor Delivery and Silencing Activity Relative to Polyethylene Glycol

Abstract

Although siRNA-based nanomedicines hold promise for cancer treatment, conventional siRNA–polymer complex (polyplex) nanocarrier systems have poor pharmacokinetics following intravenous delivery, hindering tumor accumulation. Here, we determined the impact of surface chemistry on the in vivo pharmacokinetics and tumor delivery of siRNA polyplexes. A library of diblock polymers was synthesized, all containing the same pH-responsive, endosomolytic polyplex core-forming block but different corona blocks: 5 kDa (benchmark) and 20 kDa linear polyethylene glycol (PEG), 10 kDa and 20 kDa brush-like poly(oligo ethylene glycol), and 10 kDa and 20 kDa zwitterionic phosphorylcholine-based polymers (PMPC). In vitro, it was found that 20 kDa PEG and 20 kDa PMPC had the highest stability in the presence of salt or heparin and were the most effective at blocking protein adsorption. Following intravenous delivery, 20 kDa PEG and PMPC coronas both extended circulation half-lives 5-fold compared to 5 kDa PEG. However, in mouse orthotopic xenograft tumors, zwitterionic PMPC-based polyplexes showed highest in vivo luciferase silencing (>75% knockdown for 10 days with single IV 1 mg/kg dose) and 3-fold higher average tumor cell uptake than 5 kDa PEG polyplexes (20 kDa PEG polyplexes were only 2-fold higher than 5 kDa PEG). These results show that high molecular weight zwitterionic polyplex coronas significantly enhance siRNA polyplex pharmacokinetics without sacrificing polyplex uptake and bioactivity within tumors when compared to traditional PEG architectures.

Zwitterionic polymer ligands: an ideal surface coating to totally suppress protein-nanoparticle corona formation?

“…[16] More recently, other hydrophilic polymers have been proposed as an alternative to PEG such as polysaccharides and polybetaines. The latter belong to the zwitterionic family and have been used as solubilizing ligands for a variety of nanoparticles such as silica [17][18][19][20], gold [21][22][23][24][25][26][27][28][29][30], quantum dots (QDs) [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] , SPION [30,[47][48][49][50][51] and others. [52][53][54][55][56][57][58] Zwitterionic moieties consist of positively (quaternary ammonium in the case of betaines) and negatively charged groups linked by a small carbon chain.…”

Cancer Nano-Immunotherapy from the Injection to the Target: The Role of Protein Corona

“…This effect may be related to the observations that the presence in the PC of the third component of the complement protein (C3) affects the immune cell recognition of nanomedicines [98][99][100]. To avoid the nanomaterial-induced complement activation, many researchers have used highly biocompatible materials such as zwitterionic polymers as well as hydrophilic nanoparticles which decrease the protein adsorption [101], and biomaterials already wrapped with "self" proteins such as CD200 [102]. More recently, cell membrane coatings have emerged as a new class of coatings that enable the camouflage of NPs for evading immune clearance and lessen the complement activation by nanoparticles [10,103,104].…”

Matrix-targeted Nanoparticles for MMP13 RNA Interference Blocks Post-Traumatic Osteoarthritis

“…For in vitro luciferase knockdown assays, ATDC5 cells were lentivirally transduced with 9 constitutively-expressed luciferase gene in a manner previously described (37). Cells were then 10 seeded at 2,000 per well in 96-well black plates, clear-bottom.…”

“…The clinical utility of siRNA medicines has 12 been validated by the recent clinical trial success and FDA approval of both Alnylam's 13 ONPATTRO™ (patisiran) for treatment of hereditary transthyretin-mediated amyloidosis and 14 GIVLAARI™ (givosiran) for acute hepatic porphyria (32,33). Here, we extended polymeric 15 siRNA nanopolyplexes (siNPs) recently innovated by our research group (34)(35)(36)(37) to develop the 16 first targeted form of this carrier that binds to sites of early OA cartilage damage using a collagen 17 type 2 monoclonal antibody (mAbCII). Cartilage CII is more exposed and accessible for binding 18 after injury (38), and the mAbCII antibody has previously been used as a targeted nano-diagnostic 19 for intravitally measuring severity of OA (39).…”