No abstract

Polymer therapeutics have shown promise as tumor-targeted drug delivery systems in mice. The multivalency of polymers allows the attachment of different functional agents to a polymeric backbone, including chemotherapeutic and antiangiogenic drugs, as well as targeting moieties, such as the bone-targeting agent alendronate (ALN). We previously reported the conjugation of ALN and the chemotherapeutic drug paclitaxel (PTX) with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. The in vitro physicochemical properties, cancer cytotoxicity and antiangiogenic activity of HPMA copolymer-PTX-ALN conjugate were extensively characterized. The reported results warranted in vivo evaluations of the conjugate. In this manuscript, we evaluated the in vivo anticancer and antiangiogenic activity of HPMA copolymer-PTX-ALN conjugate. The conjugate exhibited an antiangiogenic effect by decreasing microvessel density (MVD), and inducing apoptotic circulating endothelial cells (CEC) following treatment of the mice. Using intravital imaging system and mCherry-labeled breast cancer cell lines, we were able to monitor noninvasively the progression of orthotopic metastatic tumors injected into the tibia of the mice. HPMA copolymer-PTX-ALN conjugate showed the greatest antitumor efficacy on mCherry-labeled 4T1 mammary adenocarcinoma inoculated into the tibia, as compared with PTX alone or in combination with ALN. Treatment with the bone-targeted polymeric conjugate demonstrated improved efficacy, was better tolerated, and was more easily administered intravenously than the clinically used PTX formulated in Cremophor/ethanol.

No abstract

No abstract

No abstract

No 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.

No abstract