Comparison of Active and Passive Targeting of Docetaxel for Prostate Cancer Therapy by HPMA Copolymer–RGDfK Conjugates

Abstract

N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-docetaxel-RGDfK conjugate was synthesized, characterized, and evaluated in vitro and in vivo in comparison with untargeted low and high molecular weight HPMA copolymer-docetaxel conjugates. The targeted conjugate was designed to have a hydrodynamic diameter below renal threshold to allow elimination post treatment. All conjugates demonstrated the ability to inhibit the growth of DU145 and PC3 human prostate cancer cells and the HUVEC at low nanomolar concentrations. The targeted conjugate showed active binding to αvβ3 integrins in both HUVEC and DU145 cells, whereas the untargeted conjugate demonstrated no evidence of specific binding. Efficacy at two concentrations (20 mg/kg and 40 mg/kg) was evaluated in nu/nu mice bearing DU145 tumor xenografts treated with a single dose of conjugates and compared with controls. RGDfK targeted and high molecular weight nontargeted conjugates exhibited the highest antitumor efficacy as evaluated by tumor regression. These results demonstrate that αvβ3 integrin targeted polymeric conjugates with improved water solubility, reduced toxicity and ease of elimination post treatment in vivo are promising candidates for prostate cancer therapy.

Preparation, characterization, and antitumor activities of folate-decorated docetaxel-loaded human serum albumin nanoparticles

“…High-affinity folate-binding protein was characterized in human hepatoma cell line SMMC-7721, and folic acid binds to the membrane fraction that cross reacts with the anti-intestines-specific membrane antigen antibody. Therefore, we firmly believed that the DTX-FA-HSANPs with smaller hydrodynamic size would have higher cellular uptake efficiency (Mi et al, 2011;Ray et al, 2011).…”

Polymer-Drug Nanoconjugate – An Innovative Nanomedicine: Challenges and Recent Advancements in Rational Formulation Design for Effective Delivery of Poorly Soluble Drugs

“…For example HPMA copolymers containing cyclic Arg-GlyAsp peptides have been developed for targeting αvβ3 integrins expressed on angiogenic tumor blood vessels and other tumor cells. The anticancer and antiangiogenic agent, geldanamycin (aminohexylgeldanamycin), was conjugated to the polymer backbone through a lysosome-degradable GFLG (Gly-Phe-Leu-Gly) linker and the molecular weight was maintained at 40 kDa to ensure renal clearance after administration (112)(113)(114)(115)(116). The authors reported significantly higher localization of drug-loaded HPMA copolymer containing the arginylglycylaspartic acid (RGD) peptide (target moiety) in tumour cells and tumour growth suppression in prostate cancer bearing mice compared to control without a targeting moiety.…”

Dual-targeting delivery system for bone cancer: synthesis and preliminary biological evaluation

“…The RGD sequence, an arginine-glycine-aspartic (Arg-Gly-Asp) tripeptide, has been identified as a high affinity α v β 3 selective ligand (Ray et al, 2011). The α v β 3 , one of the integrin receptor family, is proved to be overexpressed on the angiogenic endothelium in malignant or diseased tissues (Temming et al, 2007;Barczyk et al, 2010), and it is also an important marker of blood vessels in the most malignant tumors, all of which make it an attractive target for antitumors strategy (Murphy et al, 2008).…”

“…The α v β 3 , one of the integrin receptor family, is proved to be overexpressed on the angiogenic endothelium in malignant or diseased tissues (Temming et al, 2007;Barczyk et al, 2010), and it is also an important marker of blood vessels in the most malignant tumors, all of which make it an attractive target for antitumors strategy (Murphy et al, 2008). As a result, the conjugate modified with RGD demonstrates extraordinary potential to target drug to the tumors (Ray et al, 2011;Xu et al, 2012). In addition, the α v β 3 is also highly expressed in bone metastatic cells and osteoclasts, so that the α v β 3 integrin is also an attractive target for bone (Teti et al, 2002).…”