Development of PEGylated doxorubicin‐E‐[c(RGDfK)₂] conjugate for integrin‐targeted cancer therapy

Abstract

Doxorubicin (DOX) is extensively used in cancer therapy; however, it is cardiotoxic in cumulative doses and chemoresistance can evolve with prolonged use. Conjugation of a chemotherapeutic agent to a water‐soluble polymeric carrier prolongs the circulation life of the drug, promotes its accumulation at the tumor site due to the enhanced permeability and retention (EPR) effect and prevents the drug from extravasating into healthy tissues. We designed and synthesized a delivery system that enables the conjugation of a targeting moiety, Arg‐Gly‐Asp (RGD) peptidomimetic, on one end of a linear poly(ethylene glycol) (PEG) chain, and DOX on the other end. The drug was bound to the polymer through an acid‐sensitive (6‐maleimidocaproyl)hydrazone linker. The resulting PEG‐DOX‐E‐[c(RGDfK)2] conjugate actively and selectively targets endothelial and tumor cells overexpressing αvβ3 integrin. Alternatively, we conjugated the PEG‐DOX with a control c(RADfK) peptide that does not bind to αvβ3 integrin, resulting in a PEG‐DOX‐c(RADfK) conjugate. The PEG‐DOX‐E‐[c(RGDfK)2] conjugate and free DOX exhibited similar cytotoxic effect on U87‐MG human glioblastoma cells. Interestingly, treatment with the conjugate inhibited the proliferation of DOX‐resistant M109 murine lung carcinoma cells at a lower IC50 compared with free DOX and PEG‐DOX‐c(RADfK). In addition, PEG‐DOX‐E‐[c(RGDfK)2] inhibited the proliferation of human umbilical vein endothelial cells and their attachment to fibrinogen‐coated wells. Preliminary in vivo near‐infrared studies revealed that a PEG‐E‐[c(RGDfK)2]‐cyanine conjugate preferentially accumulated in mCherry‐labeled‐DA3 murine mammary tumors inoculated orthotopically in female BALB/c mice. Altogether, our results show a proof of principle for a selective delivery of DOX to endothelial and cancer cells overexpressing αvβ3 integrin. Copyright © 2010 John Wiley & Sons, Ltd.

‘Living’ PEGylation on gold nanoparticles to optimize cancer cell uptake by controlling targeting ligand and charge densities

“…Consequently, we synthesized HS-PEG-RGD to investigate specific targeting efficacy of AuNPs to α v β 3 integrin receptors. The targeting peptide conjugation to PEG was performed based on traditional coupling reactions between NHS ester and amine groups using thiol-protected OPSS-PEG-NHS and cyclo(RGDfk)-NH 2 followed by deprotection of the thiol groups using DTT (Scheme S2) [39, 40]. The expected HS-PEG-RGD was purified by a size exclusion column and confirmed by HPLC, with the retention time shifting from 16.87 to 19.64 min compared to unconjugated RGD (Figure S5) [42].…”

Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel

“…To obtain semi-quantitative results, the number of cycles for each reaction was calibrated and kept to a minimum. M109 cDNA was used as a positive control [30]. PCR primers: Mouse β3 Integrin: 5′-AAGCACTGGGTGGTGATTG -3′, 5′-TGAGGTCAAGGTGTGTGA -3′; GAPDH (mouse): 5′-CCATCACCATCTTCCAGGAGC -3′, 5′-GGCATGGACTGTGGTCATGAG -3′.…”

Receptor Mediated Cellular Uptake of Low Molecular Weight Dendritic Polyglycerols

“…45 On the other hand, LHRH analogs are used in the treatment of hormone-dependent tumors, such as the prostate carcinoma and the estrogen receptor-positive mamma carcinoma for the pharmacological suppression of the sexual hormones. 46 Ovarian and endometrium carcinoma cells express the LHRH receptors.…”