Activity and Tissue Distribution of Antisense Oligonucleotide CT102 Encapsulated with Cytidinyl/Cationic Lipid against Hepatocellular Carcinoma

Abstract

Insulin-like growth factor 1 receptor (IGF1R), a cell surface receptor with tyrosine kinase (TK) activity, has ligands abnormally expressed in acute leukemia, multiple myeloma, breast, prostate, cervical, and nonsmall cell lung cancers, Ewing's sarcoma, and other malignant tumors. IGF1R mediates the malignant proliferation, invasion, and metastasis of tumor cells through a variety of signal transduction pathways, and it is also involved in tumor angiogenesis and tumor cell antiapoptosis. In this study, the neutral cytidinyl lipid DNCA and cystine skeleton cationic lipid CLD from our laboratory could be optimized to encapsulate antisense oligonucleotide (ASO) CT102 to form stable and uniform Mix/CT102 nanoparticles (NPs), which could specifically target tumor cells that highly expressed IGF1R in vivo by intravenous administration. Compared with naked CT102, the lipid complex could promote the uptake and late apoptosis levels of HepG2 and Huh-7 cells, inhibiting cell proliferation efficiently. We also found that Mix/CT102 could enter nucleus in about 2 h, effectively downregulating the mRNA level of IGF1R. The in vivo efficacy experiment demonstrated that in the group that received the optimal dose of Mix/CT102, tumor volume was reduced 8-fold compared with the naked dose group. Meanwhile, in vivo distribution studies showed that the nanoparticles had a predominant accumulation capacity in liver tissue. These results indicated that clinicians can expect the Mix/CT102 nanocomposite to be very effective in reducing the dose and frequency of clinically administered CT102, thereby reducing the side effects of ASOs.

Modified ASO conjugates encapsulated with cytidinyl/cationic lipids exhibit more potent and longer-lasting anti-HCC effects

“…Based on previous work, 44 an appropriate molar ratio of carriers (lipid/antisense oligonucleotide [ASO] = 60:1) was preliminarily determined. In this study, the composition ratio of DNCA/CLD was changed to 60:0 (termed DNCA), 40:20 (termed Mix-1), 30:30 (termed Mix), and 20:40 (termed Mix-2) to explore the influence of the formulation ratio on the distribution characteristics in vivo .…”

“…Compared with sorafenib, DCP-CT102 achieved greater efficacy at a dose of ∼2 mpk administered every other day. 44 …”

The Method of Viral Mimicry in Oncology and Prospects for its Improvement

“…Основой для проектирования АСО, направленных на специфические РЭ, могут стать уже имеющиеся сведения об использовании в онкологии АСО, направленных на микроРНК (которым могли произойти в эволюции от РЭ) [42], онкогены или онкосупрессоры (поскольку они характеризуются тесной взаимосвязью с РЭ [69]. Так, предложены АСО, нац еленные на 11 экзон онкосупрессорного гена NF2 при нейрофиброматозе 2-го типа [70], на FLT3-ITD (онкогенная fms-подобная тирозинкиназа 3) и микроРНК miR-125b при остром миелобластном лейкозе [2], на микроРНК miR-17 (для μ-17-ON), miR-21 (для μ-21-ON) и miR-155 (для μ-155-ON) при лимфосаркоме [71], на онкогенны IGF1R (рецептор инсулиноподобного фактора роста) [72], супрессоры опухолей Smad7 [73], Stat3 при гепатоцеллюлярной карциноме [74], онкогенный трансформирующий фактор роста TGF-β2 при раке легкого [75] и ТНРМЖ [76].…”

Nonviral delivery systems for antisense oligonucleotide therapeutics

“…LNPs have a suitable particle size (diameter range of 10-500 nm) combined with their own biocompatible and biodegradable lipids, which enables LNPs-ASOs to escape uptake by the mononuclear phagocyte system (MPS), subsequently prolonging the circulation time of LNPs-ASOs and allowing the particles to passively and efficiently target cells through an enhanced permeability and retention effect to release ASOs [45][46][47]. They also improve cell-to-ASO uptake by inducing lipid fusion between the membranes of LNPs and target cells during structure phase transitions [48][49][50], and help ASOs travel to target genes by promoting endosomal escape after cellular uptake [50,51]. Examples of lipid-based delivery systems that effectively deliver ASOs are summarized in Table 2.…”