Tumor-Specific Anti-Nucleosome Antibody Improves Therapeutic Efficacy of Doxorubicin-Loaded Long-Circulating Liposomes against Primary and Metastatic Tumor in Mice

Abstract

The efficacy of drug delivery systems can be significantly enhanced by making them target-specific via the attachment of various ligands to their surface. We attempted to enhance tumor accumulation and therapeutic effect of doxorubicin-loaded long-circulating liposomes (Doxil ® , ALZA Corp.) by coupling to their surface the anti-cancer monoclonal antibody 2C5 (mAb 2C5) with nuclesome (NS)-restricted activity, that can recognize the surface of various tumor but not normal cells via the surfacebound nucleosomes released from the apoptotically dying neighboring tumor cells and specifically targets pharmaceutical carriers to tumor cells in vitro and in vivo. Antibody coupling to PEGylated doxorubicin-liposomes was performed by the "post-insertion" technique. The pharmacokinetics of plain and immuno-targeted Doxil ® -mimicking liposomes, as well as their accumulation in primary Lewis Lung Carcinoma (LLC) tumors in mice was followed by real-time gamma-scintigraphy upon liposomal membrane labeling with 111 In. Therapeutic action of various liposomal formulations was followed by registering primary tumor growth, determining tumor weigh upon mice sacrifice, and by counting the number of metastases in the liver and lungs. 2C5 antibody-targeted liposomes demonstrate significantly enhanced accumulation in LLC tumors. Targeted doxorubicin-loaded PEG-liposomes were significantly more effective in inhibiting tumor growth and metastatic process in the LLC tumor models in mice. Our results clearly show the remarkable capability of 2C5-targeted Doxil ® to specifically deliver its cargo into various tumor manifestations (solid and metastatic) significantly increasing the efficacy of therapy.

Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise for use in drug-resistant cancer therapy

“…The loading efficiency of DXR in liposomes was determined by measuring the fluorescence of DXR (Ex=450 nm, Em=590 nm) of prepared liposomes following treatment with MeOH to disrupt the liposome structure. Doxil (doxorubicin encapsulated in small sized liposomes) were prepared as described previously [15].…”

Targeted intracellular codelivery of chemotherapeutics and nucleic acid with a well-defined dendrimer-based nanoglobular carrier

“…The G3 nanoglobule, (L-Lysine) 32 -(L-lysine) 16 -(L-lysine) 8 -OAS, was synthesized as described earlier (10). G3 (89.0 mg, 5.8 mmol), HOBT (13.4 mg, 0.99 mmol) and HBTU (37.6 mg, 0.99 mmol) were dissolved in DMF (1 ml) and 3-mercaptopropanoic acid (MPA) (3.23 ml, 37 mmol) was separately diluted in DMF (0.2 ml).…”

“…However, they suffer various limitations for drug delivery. Liposomes have a relatively large payload, but formulation of liposomal delivery systems is relatively complicated and the surface of liposomes needs to be modified with biocompatible polymers to minimize non-specific tissue uptake [8]. Synthetic biocompatible macromolecules can accommodate different therapeutic agents for codelivery, but most of the synthetic macromolecules are mixtures of polymers of different sizes and do not have uniform and constant morphology before and after chemical modifications, which may complicate their pharmacokinetic properties during in vivo applications [9].…”

Antibody-Targeted Nanoparticles for Cancer Treatment

“…The 2C5 Ab specifically recognises extracellular and tumour-cell bound nucleosomes that arise from apoptotic tumour cells in-vivo [75]. Even when used at subtherapeutic quantities, 2C5 is an effective tumour targeting moiety for PLD, also showing efficacy against primary and metastatic lung tumours in mice [75].…”

“…The 2C5 Ab specifically recognises extracellular and tumour-cell bound nucleosomes that arise from apoptotic tumour cells in-vivo [75]. Even when used at subtherapeutic quantities, 2C5 is an effective tumour targeting moiety for PLD, also showing efficacy against primary and metastatic lung tumours in mice [75]. Central nervous system (CNS) tumours present a unique challenge to treatment due to the presence of the blood brain barrier (BBB); a unique physiological barrier which functions to protect the brain but also limits drug delivery to the CNS [83].…”