Combination Chemotherapy of L1210 Tumors in Mice with Pretubulysin and Methotrexate Lipo-Oligomer Nanoparticles

Abstract

In the current study, nanoparticles containing the antimetabolite drug methotrexate (MTX) and the novel tubulin-binding drug pretubulysin (PT) were developed for combination chemotherapy. Polyelectrolyte complexes were formed based on ∼20 nm cationic nanomicelles of lipo-oligomer 454 with the anionic MTX at the molar ratio of 3:1, resulting in spherical nanoparticles with sizes of 150 nm (454 MTX). Particle formation in the presence of PT, which also interacts with 454, resulted in coloaded micelle complexes (454 PT+MTX) of 170 nm as demonstrated by transmission electron microscopy and dynamic light scattering measurements. Both drugs were incorporated to a high extent (∼85% for MTX, ∼70% for PT). Nanoparticles were stable in up to 20% serum and physiological NaCl solution. Cellular internalization of 454 PT+MTX into L1210 leukemia and KB cervix carcinoma cells was determined by confocal light scattering microscopy. The antitumor activity of the drug combination PT+MTX in both cell lines was strongly increased by drug formulation with 454 with IC50 values of PT+MTX decreasing 11-fold from 0.22 nM to 19 pM on L1210 cells and 6-fold from 2.8 to 0.48 nM on KB cervix carcinoma cells. Systemic treatment of NMRI nu/nu mice bearing subcutaneous L1210 tumors with 454 PT+MTX nanoparticles resulted in a more effective delay of tumor growth in comparison to the free drug combination of PT+MTX without 454. Importantly, nanoparticle formulation of PT+MTX with 454 increased the survival of mice by more than 100% compared to that of the buffer treated group and more than 40% compared to that of the free drug group.

Molecular recognition-driven supramolecular nanoassembly of a hydrophobic uracil prodrug and hydrophilic cytarabine for precise combination treatment of solid and non-solid tumors

“…In addition to solid tumors, chemotherapy plays a more important role in the clinical treatment of non-solid tumors, such as leukemia. 28 We further investigated the anticancer efficacy of U : C NPs against leukemia. The DBA/2 mice inoculated with L1210 cells were utilized to study the anticancer efficacy of the supramolecular nanoassembly against nonsolid tumors (Fig.…”

Delivery of Cas9/sgRNA Ribonucleoprotein Complexes via Hydroxystearyl Oligoamino Amides

“…Sequence-defined oligo(ethylenamino) amides (OAAs) based on artificial oligoamino acids and solid-phase synthesis have recently been developed as a platform for the delivery of nucleic acids, 30 proteins, 16 and drugs. 31 They combine the advantages of aminoethylene-based polymers 32,33 with the chemical precision of peptides and enable cargo-specific optimization. 34 OAAs with a favorable stability, biocompatibility, and toxicity profile have been generated.…”

Binary Nanodrug-Delivery System Designed for Leukemia Therapy: Aptamer- and Transferrin-Codecorated Daunorubicin- and Luteolin-Coloaded Nanoparticles

“…HL60 cells(10 6 cells in 150 μL PBS) were injected subcutaneously into the left flank of BALB/c nude mice to produce the murine leukemia model. Tumor size was measured with a caliper and determined: L × W 2 /2 (L, longest side of the tumor; W, widest side vertical to L) 32. After tumor growth to about 100 mm 3 , mice were randomly divided into ten groups (n=8), then AP/Tf-Drn/Lut NPs (Drn 5 mg and Lut 2 mg per kg), AP-Drn/Lut NPs (Drn 5 mg and Lut 2 mg per kg), Tf-Drn/Lut NPs (Drn 5 mg and Lut 2 mg per kg), AP-Drn NPs (Drn 10 mg per kg), Tf-Lut NPs (Lut 4 mg per kg), AP/Tf NPs, free Drn/Lut (Drn 5 mg and Lut 2 mg per kg), free Drn (10 mg per kg), free Lut (4 mg per kg), and 0.9% saline solution were intravenously injected in the mice on days 0,3, 6, 9, 12, 15, 18, and 21.…”