Antibody Targeting of Camptothecin-Loaded PLGA Nanoparticles to Tumor Cells

Abstract

Antibody targeting of drug substances can improve the efficacy of the active molecule, improving distribution and concentration of the drug at the site of injury/disease. Encapsulation of drug substances into polymeric nanoparticles can also improve the therapeutic effects of such compounds by protecting the molecule until its action is required. In this current study, we have brought together these two rationales to develop a novel immuno-nanoparticle with improved therapeutic effect against colorectal tumor cells. This nanoparticle comprised a layer of peripheral antibodies (Ab) directed toward the Fas receptor (CD95/Apo-1) covalently attached to poly(lactide-co-glycolide) nanoparticles (NP) loaded with camptothecin. Variations in surface carboxyl density permitted up to 48.5 microg coupled Ab per mg of NP and analysis of nanoparticulate cores showed efficient camptothecin loading. Fluorescence visualization studies confirmed internalization of nanoconstructs into endocytic compartments of HCT116 cells, an effect not evident in NP without superficial Ab. Cytotoxicity studies were then carried out against HCT116 cells. After 72 h, camptothecin solution resulted in an IC 50 of 21.8 ng mL (-1). Ab-directed delivery of NP-encapsulated camptothecin was shown to be considerably more effective with an IC 50 of 0.37 ng mL (-1). Calculation of synergistic ratios for these nanoconstructs demonstrated synergy of pharmacological relevance. Indeed, the results in this paper suggest that the attachment of anti-Fas antibodies to camptothecin-loaded nanoparticles may result in a therapeutic strategy that could have potential in the treatment of tumors expressing death receptors.

Concepts and practices used to develop functional PLGA-based nanoparticulate systems

“…Similarly, a cell-specific and targeted delivery was achieved using anti-Fas targeted camptothecin-containing PLGA nanoparticles. 145 The success of PLGA immunonanoparticles often depends on how well an mAb is engineered onto the surface of nanoparticles. For example, Obemajer et al loaded cystatin into PLGA nanoparticles and modified the surface of the nanoparticles with anti-cytokeratin mAb to target cytokeratin on the membrane of breast tumor cells.…”

Advanced Engineering Approaches in the Development of PLGA-Based Nanomedicines

“…The reaction is catalyzed by a carbodiimide to form an amine-reactive O-acylisourea intermediate with PLGA, and [20], R-phycoerythrin conjugated monoclonal anti-human CD8 mouse immunoglobulin G [9], MAb antihuman Fas receptor (CD95/Apo-1) [56], and anti-EGFR [1]. For example, PLGA NPs loaded with CPT and covalently attached to the anti-Fas receptor CD95/Apo-1 were developed for targeting colorectal tumor cells overexpressing the Fas receptor onto their surface, a member of the tumor necrosis factor (TNF) family [56]. The immunonanoparticles were effectively internalized by HCT116 cells via endocytosis.…”

“…MAbs are introduced to the surface of PLGA NPs by covalent attachment including a chemical reaction between thiolated antibodies and maleimide groups on the surface of the NPs [46], by the reaction between free -NH 2 groups of the antibody, and surface-exposed -COOH of the NP taking advantage of the carbodiimide/ NHS chemistry [56,1,9,49,26], or through simple physical adhesion by means of an electrostatic interaction between the positively charged antibody macromolecules and the negatively charged surface of PLGA [76,55].…”

Application of traditional Chinese medicine preparation in targeting drug delivery system

“…According to the carriers, activetargeting preparation can be divided into modified liposomes, micro-emulsions, microspheres and nanoparticles, etc. (Bromberg et al, 2003;Cheng et al, 2007;Homhuan et al, 2007;Bakowsky et al, 2008;Mccarron et al, 2008;Min et al, 2008;Cao et al, 2009;Shen et al, 2009;Werle et al, 2009;Weber, 2010;Botella et al, 2011;Devarajan & Ravichandran, 2011). Tian et al (2010) using the specific receptor-ligand combination principle on the surface of tumor cells, established a liver-targeted drug delivery carrier, which was composed of chitosan/poly(ethylene glycol)-glycyrrhetinic acid nanoparticles.…”