Novel reduction‐sensitive micellar nanoparticles assembled from Rituximab–doxorubicin conjugates as smart and intuitive drug delivery systems for the treatment of non‐Hodgkin's lymphoma

Abstract

In this study, a novel reduction-sensitive drug delivery system, the rituximab-doxorubicin (RTX-DOX) micellar nanoparticle (RDMN), was specially designed for targeted delivery and release of DOX in non-Hodgkin's lymphoma (NHL) cells. The RDMN was fabricated by self-assembling of amphiphilic RTX-DOX conjugates (RDCs), which were synthesized by conjugating the hydrophilic Fab fragments of RTX (an anti-CD20 monoclonal antibody) and hydrophobic DOXs by a reduction-responsive linker, 3-(2-Pyridyldithio) propionyl hydrazide (PDPH). The RDMNs were characterized via dynamic light scattering and transmission electron microscopy, both showed the sizes of approximately 94.1 ± 14.5 nm with a uniform size distribution. Polyplex dissociation, which was indicated by accelerated DOX release rate and increased particle size, was observed in the presence of 2.5 mm 1,4-dithiothreitol due to the cleavage of disulfide bonds in PDPH linkers. In vitro transfection assays against human NHL cell line, JeKo-1, showed significantly increased uptake for RDMNs, as compared to RDCs and free RTX/DOX. Both in and ex vivo experiments demonstrated that RDMNs showed the highest therapeutic effect among all the experimental groups. These results suggested that this RDMN could be a potential, safe and efficient drug delivery vector, which deserves further investigation in the clinic.

Past, Present, and Future of Rituximab—The World’s First Oncology Monoclonal Antibody Therapy

“…Ritixumab conjugated to doxorubicin is one example of toxin conjugated anti-CD20 therapy. This strategy has been further modified to improve efficacy, including attempts to generate reduction-sensitive micellar nanoparticles for better delivery, although neither these nor any similar anti-CD20 conjugate with toxins, have been approved by the FDA to date ( 89 ).…”

<p>How the discovery of rituximab impacted the treatment of B-cell non-Hodgkin&rsquo;s lymphomas</p>

“…Toxin-conjugated anti-CD20 therapy initially showed higher response rates as the toxic payload was delivered directly to B-cell malignancies, but was eventually pulled from the market, due to poor sales 71. Current work in this field includes rituximab–doxorubicin therapy; however, this has not been approved by the FDA 72. Furthermore, additional therapeutic anti-CD20 MoAbs have been generated featuring modifications including an alternate binding epitope, additional humanization, or altered glycosylation.…”