A Rationally Optimized Nanoparticle System for the Delivery of RNA Interference Therapeutics into Pancreatic Tumors in Vivo

Abstract

Pancreatic cancer is a devastating disease with a dismal prognosis. Short-interfering RNA (siRNA)-based therapeutics hold promise for the treatment of cancer. However, development of efficient and safe delivery vehicles for siRNA remains a challenge. Here, we describe the synthesis and physicochemical characterization of star polymers (star 1, star 2, star 3) using reversible addition-fragmentation chain transfer polymerization (RAFT) for the delivery of siRNA to pancreatic cancer cells. These star polymers were designed to contain different lengths of cationic poly(dimethylaminoethyl methacrylate) (PDMAEMA) side-arms and varied amounts of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA). We showed that star-POEGMA polymers could readily self-assemble with siRNA to form nanoparticles. The star-POEGMA polymers were nontoxic to normal cells and delivered siRNA with high efficiency to pancreatic cancer cells to silence a gene (TUBB3/βIII-tubulin) which is currently undruggable using chemical agents, and is involved in regulating tumor growth and metastases. Notably, systemic administration of star-POEGMA-siRNA resulted in high accumulation of siRNA to orthotopic pancreatic tumors in mice and silenced βIII-tubulin expression by 80% at the gene and protein levels in pancreatic tumors. Together, these novel findings provide strong rationale for the use of star-POEGMA polymers as delivery vehicles for siRNA to pancreatic tumors.

Delineating the Role of βIV-Tubulins in Pancreatic Cancer: βIVb-Tubulin Inhibition Sensitizes Pancreatic Cancer Cells to Vinca Alkaloids

“…In fact, the ability of βIVb-tubulin inhibition to sensitize PDA cells to vinca alkaloids also means that vinca alkaloid dosing could potentially be reduced in combination with βIVb-tubulin inhibition. We have also made significant advances in siRNA delivery technology [37], which not only overcomes the lack of specific inhibitors against βIVb-tubulin, but can also target therapy to PDA tumors. To highlight the therapeutic potential of targeting a single β-tubulin isotype up-regulated in PDA, we have previously administered therapeutic doses of βIII-tubulin siRNA with nanoparticle which effectively inhibited βIII-tubulin protein levels in orthotopic pancreatic tumors without any off-target toxicity in other organs in mice [37].…”

MutY-Homolog (MYH) inhibition reduces pancreatic cancer cell growth and increases chemosensitivity

“…Moreover, MYH knockout mice, while viable, are 1.7 times more likely to develop spontaneous tumours, particularly in the intestines [35]. On this point, siRNA therapeutics coupled to cancer-targeting nanoparticles represent an ideal avenue for targeting MYH in PC cells, while overcoming the current lack of pharmacological inhibitors against MYH [36–38]. …”

Synthesis of Star Polymers by RAFT Polymerization as Versatile Nanoparticles for Biomedical Applications

“…Notably, further in vivo studies have revealed a bright future for star polymers in gene therapy. [41,42] In addition to the biomedical applications noted in the present review, star polymers can also be employed in several other fields such as membrane science, catalysis, and photonics. Given the variety of potential applications for these versatile materials, we envision that, going forward, star polymers prepared using RAFT polymerization will continue to be the subject of considerable interest.…”

“…After systemic administration, the in vivo results indicated that the star polymer could efficiently deliver siRNA to orthotopic pancreatic tumours in mice and effectively inhibit the expression of bIIItubulin. [42] Notably, the gene delivery capability of PDMAEMA-based cationic star polymers was not compromised by employing other synthetic protocols for the star formation, such as an ATRP arm-first approach. [43] Compared with other drug and gene carriers self-assembled from amphiphilic molecules, the synthesis of star polymers is both time-and cost-effective.…”