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1.
Tumour Biol ; 39(5): 1010428317701628, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28468593

RESUMO

Peritoneal carcinomatosis results from dissemination of solid tumors in the peritoneal cavity, and is a common site of metastasis in patients with carcinomas of gastrointestinal or gynecological origin. Peritoneal carcinomatosis treatment is challenging as poorly vascularized, disseminated peritoneal micro-tumors are shielded from systemic anticancer drugs and drive tumor regrowth. Here, we describe the identification and validation of a tumor homing peptide CKRDLSRRC (IP3), which upon intraperitoneal administration delivers payloads to peritoneal metastases. IP3 peptide was identified by in vivo phage display on a mouse model of peritoneal carcinomatosis of gastric origin (MKN-45P), using high-throughput sequencing of the peptide-encoding region of phage genome as a readout. The IP3 peptide contains a hyaluronan-binding motif, and fluorescein-labeled IP3 peptide bound to immobilized hyaluronan in vitro. After intraperitoneal administration in mice bearing peritoneal metastases of gastric and colon origin, IP3 peptide homed robustly to macrophage-rich regions in peritoneal tumors, including poorly vascularized micro-tumors. Finally, we show that IP3 functionalization conferred silver nanoparticles the ability to home to peritoneal tumors of gastric and colonic origin, suggesting that it could facilitate targeted delivery of nanoscale payloads to peritoneal tumors. Collectively, our study suggests that the IP3 peptide has potential applications for targeting drugs, nanoparticles, and imaging agents to peritoneal tumors.


Assuntos
Carcinoma/tratamento farmacológico , Receptores de Hialuronatos/administração & dosagem , Peptídeos/administração & dosagem , Neoplasias Peritoneais/tratamento farmacológico , Animais , Bacteriófagos/genética , Carcinoma/genética , Carcinoma/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Humanos , Receptores de Hialuronatos/genética , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Metástase Neoplásica , Peptídeos/genética , Cavidade Peritoneal/patologia , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/patologia
2.
Biomaterials ; 104: 247-57, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27472162

RESUMO

Polymersomes are versatile nanoscale vesicles that can be used for cytoplasmic delivery of payloads. Recently, we demonstrated that pH-sensitive polymersomes exhibit an intrinsic selectivity towards intraperitoneal tumor lesions. A tumor homing peptide, iRGD, harbors a cryptic C-end Rule (CendR) motif that is responsible for neuropilin-1 (NRP-1) binding and for triggering extravasation and tumor penetration of the peptide. iRGD functionalization increases tumor selectivity and therapeutic efficacy of systemic drug-loaded nanoparticles in many tumor models. Here we studied whether intraperitoneally administered paclitaxel-loaded iRGD-polymersomes show improved efficacy in the treatment of peritoneal carcinomatosis. First, we demonstrated that the pH-sensitive polymersomes functionalized with RPARPAR (a prototypic CendR peptide) or iRGD internalize in the cells that express NRP-1, and that internalized polymersomes release their cargo inside the cytosol. CendR-targeted polymersomes loaded with paclitaxel were more cytotoxic on NRP-1-positive cells than on NRP-1-negative cells. In mice bearing peritoneal tumors of gastric (MKN-45P) or colon (CT26) origin, intraperitoneally administered RPARPAR and iRGD-polymersomes showed higher tumor-selective accumulation and penetration than untargeted polymersomes. Finally, iRGD-polymersomes loaded with paclitaxel showed improved efficacy in peritoneal tumor growth inhibition and in suppression of local dissemination compared to the pristine paclitaxel-polymersomes or Abraxane. Our study demonstrates that iRGD-functionalization improves efficacy of paclitaxel-polymersomes for intraperitoneal treatment of peritoneal carcinomatosis.


Assuntos
Nanocápsulas/administração & dosagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neuropilina-1/metabolismo , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacocinética , Paclitaxel/administração & dosagem , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Sinergismo Farmacológico , Infusões Parenterais , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanocápsulas/química , Nanoconjugados/administração & dosagem , Nanoconjugados/química , Paclitaxel/química , Polímeros/química , Resultado do Tratamento
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