Self-assembly of carbon nanotubes and antibodies on tumours for targeted amplified delivery

Abstract

Single-walled carbon nanotubes (SWNTs) can deliver imaging agents or drugs to tumours and offer significant advantages over approaches based on antibodies or other nanomaterials. In particular, the nanotubes can carry a substantial amount of cargo (100 times more than a monoclonal antibody), but can still be rapidly eliminated from circulation by renal filtration, like a small molecule, due to their high aspect ratio. Here we show that SWNTs can target tumours in a two-step approach in which nanotubes modified with morpholino oligonucleotide sequences bind to cancer cells that have been pre-targeted with antibodies modified with oligonucleotide strands complementary to those on the nanotubes. The nanotubes can carry fluorophores or radioisotopes, and were shown to selectively bind to cancer cells in vitro and in tumour-bearing xenografted mice. The binding process is also found to lead to antigen capping and internalization of the antibody/nanotube complexes. The nanotube conjugates were labelled with both alpha-particle and gamma-ray emitting isotopes, at high specific activities. Conjugates labelled with alpha-particle generating 225Ac were found to clear rapidly, thus mitigating radioisotope toxicity, and were shown to be therapeutically effective in vivo.

Synthesis, pharmacokinetics, and biological use of lysine-modified single-walled carbon nanotubes

“…41 The lack of a pegylated side did not affect small interfering (siRNA)-wrapping or was compensated by the additional density of the modification, proximity to the construct, or the amine environment ( Figure 7) at pH 7.4, showing similar stoichiometry (one to two siRNA per tube) and K d (1.108e-8) in the ten nanomolar range. Along with the previously mentioned animal studies, the successful wrapping of siRNA on SWCNTs, a recently proposed delivery method for gene suppression, 32 highlights the in vivo potential of modified SWCNTs.…”

“…[26][27][28][29][30][31][32] Commonly employed among 1,3-cycloadditions is the Prato reaction 33 -an adaptation of chemistry developed by Tsuge and Kanemasa 18 -which solubilizes and aminates fullerenes with a Boc (tert-Butyloxycarbonyl)-protected, pegylated pyrrolidine bearing both a primary and a tertiary amine (1) ( Figure 1A). …”

“…32,40 The majority of that activity was found in the kidneys, with lesser amounts found in the liver and digestive tract. The liver, while the primary point of accumulation for unmodified SWCNTs, is a distant second in the case of functionalized tubes, with only 0.2%-0.3% of the injected dose at 12 hours postinjection.…”

Targeted and Nontargeted α-Particle Therapies

“…To treat a lymphoma xenograft in a mouse model, Mulvey et al (106) developed a two-step pretargeting approach that utilized 225 Ac-DOTA-functionalized CNTs radiolabeled with high specific activities. In particular, an anti-CD20-MORF component was used for pretargeting, followed by the fast-clearing therapeutic [ 225 Ac]DOTA-labeled CNTs modified with a morpholino (cMORF) oligonucleotide sequence that was complementary to the pretargeted anti-CD20-MORF sequence.…”

“…In particular, an anti-CD20-MORF component was used for pretargeting, followed by the fast-clearing therapeutic [ 225 Ac]DOTA-labeled CNTs modified with a morpholino (cMORF) oligonucleotide sequence that was complementary to the pretargeted anti-CD20-MORF sequence. The improved efficacy that was observed with the two-step approach in vivo (106) was attributed to the internalization of the radiolabeled constructs. The rapid elimination in the urine of the untargeted radiolabeled construct alleviated radioisotope toxicity.…”