RESUMO
Cancer chemotherapy targeted to angiogenic vessels is expected to cause indirect tumor regression through the damage of the neovasculature without the induction of drug resistance. To develop a tool for neovasculature-specific drug delivery, we isolated novel peptides homing to angiogenic vessels formed by a dorsal air sac method from a phage-displayed peptide library. Three distinct phage clones that markedly accumulated in murine tumor xenografts presented PRPGAPLAGSWPGTS-, DRWRPALPVVLFPLH- or ASSSYPLIHWRPWAR-peptide respectively. After the determination of the epitope sequences of these peptides, we modified liposomes with epitope penta-peptides. Liposome modified with APRPG-peptide showed high accumulation in murine tumor xenografts, and APRPG-modified liposome encapsulating adriamycin effectively suppressed experimental tumor growth. Finally, specific binding of APRPG-modified liposome to human umbilical endothelial cells, and that of PRP-containing peptide to angiogenic vessels in human tumors, i.e., islet cell tumor and glioblastoma, were demonstrated. The present study indicates the usefulness of APRPG-peptide as a tool for anti-neovascular therapy, a novel modality of cancer treatment.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Melanoma Experimental/irrigação sanguínea , Neovascularização Patológica/tratamento farmacológico , Peptídeos/uso terapêutico , Sarcoma Experimental/irrigação sanguínea , Sequência de Aminoácidos , Animais , Antibióticos Antineoplásicos/farmacologia , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Humanos , Injeções Subcutâneas , Lipossomos/metabolismo , Linfocinas/farmacologia , Masculino , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal , Dados de Sequência Molecular , Neovascularização Patológica/patologia , Biblioteca de Peptídeos , Sarcoma Experimental/patologia , Tomografia Computadorizada de EmissãoRESUMO
Novel peptides homing to angiogenic vessels were recently isolated from a phage-displayed random pentadecapeptide library. One of the isolated peptides, ASSSYPLIHWRPWAR, significantly suppressed the migration of VEGF-stimulated human umbilical vein endothelial cells. Dendoric ASSSYPLIHWRPWAR-peptide suppressed the formation of new blood vessels in dorsal air sac model mice. Furthermore, ASSSYPLIHWRPWAR-peptide and the fragment peptides containing WRP, which is revealed to be an epitope sequence, significantly suppressed the tumor growth, although 15-mer shuffled peptide derived from ASSSYPLIHWRPWAR and pentapeptides with alanine substitution of each residue of WRP did not. Taken together, ASSSYPLIHWRPWAR-peptide may cause tumor dormancy through inhibition of angiogenesis, and the WRP sequence may be the minimal and essential sequence for this activity.
