Precision targeting of intraperitoneal tumors with peptide-guided nanocarriers
Date
2019-03-11
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Abstract
Seedetrakti ja günekoloogiliste pahaloomuliste kasvajate puhul on kasvajarakkude levik kõhuõõnes ehk peritoneaalne kartsinomatoos (PK) üks sagedasemaid ilminguid. PK ravivõimalused on piiratud, kuna süsteemne keemiaravi on madala efektiivsusega ning patsiendile manustatavat ravimidoosi piiravad kõrvalnähud kõhuõõnevälistes kudedes. Võrreldes intravenoossete ravimitega saavutavad otse kõhuõõnde manustatud vähiravimid kasvajakoes kõrgema kontsentratsiooni ning on oluliselt efektiivsemad. Sellegipoolest põhjustavad intraperitoneaalselt manustatud tsütotoksilised ravimid kõrvaltoimeid kõhuõõne normaalsetes kudedes.
Üheks võimaluseks ravimite ja kontrastainete efektiivsemaks muutmiseks ja kõrvalnähtude vähendamiseks on nende laadimine nanosakestesse. Nanoosakeste abil on võimalik parandada ravimite lahustuvust, koeselektiivsust ja vabanemist sihtmärkkoes.
Mõned nanoravimid PK ravimiseks on jõudnud kliiniliste uuringuteni, kuid hetkel ei ole veel ühtegi Ravimiametite poolt heaks kiidetud nanoravimit turul, mis oleks spetsiaalselt sellise manustamisviisi (st. otse kõhuõõne manustatuna) jaoks kinnitatud.
Vähiravimite ja nanoosakeste koeselektiivsuse ja efektiivsuse parandamiseks saab neid suunata keemiliselt konjugeeritud afiinsusligandidega (nt. antikehad, peptiidid, aptameerid). Meie uurimisgrupis kasutab sellel eesmärgil vähiselektiivseid peptiide, näiteks iRGD vähkipenetreerivat peptiidi (TPP). Pärast seondumist rakupinna integriinidega läbib iRGD proteolüütilise lõikamise, mis aktiveerib seondumise teise vähirakkudel üleekspresseeritud valgu, NRP-1’ga, et käivitada rakuinternalisatsiooni rada. TT1 vähkipenetreeriva peptiidi primaarne retseptor on vähirakkude pinnal ekspresseeruv valk p32, mis normaalsetes rakkudes paikneb mitokondrites. TT1 peptiid kinnitub kasvajarakkude pinnal olevale p32’le ning käivitab seejärel NRP-1’st sõltuva rakkusisenemise protsessi.
Käesolev prekliiniline töö keskendus kõhuõõne vähkkasvajate (maovähk, soolevähk ja munasarjavähk) uute kuvamis- ja ravimeetodite väljatöötamisele kasutades erinevate koostisega nanoosakesi (nanoravimid) ning suunavaid vähiselektiivseid peptiide. Töös uuriti polümeeridel põhinevate ja raudoksiidi sisaldavate nanoosakeste selektiivsust kasvajakoe suhtes peale kõhuõõnde süstimist. Katses kasutati erinevatel kõhuõõne kasvajarakkudel põhinevaid hiire loommudeleid.
Töö tulemus näitas, et vähiselektiivsete peptiidide konjugeerimine aitab kaasa nanoosakeste paremale akumulatsioonile kasvajakoes ja rakku sisenemisele. IP süstitud TPP-NP on võrreldes IV süstitud osakestega vähikoe suhtes selektiivsemad. IP manustatud TPP-NP akumuleeruvad kasvajakoes nii otsese seondumise teel kasvajarakkudele kui ka kaudselt, vereringe kaudu ning ekperimentaalteraapia hiiremudelil näitas et, nanoosakeste suunamine vähiselektiivsete peptiididega võimendab osakeste terapeutilist efektiivsust.
Gastrointestinal and gynecological malignancies often disseminate in the peritoneal cavity and cause severe complications such as bowel obstruction and the formation of ascites- a condition known as peritoneal carcinomatosis (PC). PC results from the dissemination of the primary tumor or seeding after surgical intervention and is a cause for incurability of intra-abdominal cancers. In the treatment of peritoneal tumor lesions, intraperitoneal chemotherapy can be used to improve delivery of drugs into peritoneal tumors by providing direct contact and higher local concentration, but this approach as well is not harmless and can cause side effects in the normal organs residing in the IP cavity. IP chemotherapy is an attractive strategy to improve the outcome of PC. During the last decades, substantial amount of work has been put into improving the therapeutic outcome of PC by applying different therapeutic approaches that maximize selectivity and limit side effects. Nanoparticles in the context of direct targeting of IP tumors are actively being evaluated in preclinical studies due to their potential of increasing the retention time in the IP cavity and to target drugs specifically to the tumor site compared to the conventional drugs. A few nanoparticle formulations of chemotherapeutic drugs have reached human trials, but there are no approved drug formulations for the specific use in the IP cavity. Novel strategies such as development of precision nanomedicines to specifically target cancerous lesions and development of drugs/nanoparticles with extended residence time in the IP cavity may help to increase efficacy of IP chemotherapy. The tissue selectivity and efficacy of nanoparticles and chemotherapeutic drugs can be increased by conjugating affinity ligands (i.e antibodies, peptides, aptamers) on their surface. Our lab focuses on tumor penetrating peptides (TPP), such as iRGD and TT1. The iRGD peptide is recruited to integrins expressed on endothelial cells and other cells in tumors. After recruitment to integrins, iRGD is proteolytically cleaved to expose c-terminally CRGDK CendR motif, and the truncated peptide loses most of its integrin-binding capacity and gains affinity for neuropilin-1 (NRP-1). Binding to NRP-1 mediates penetration to cells and tissues. The primary homing receptor for TT1 is p32, a mitochondrial protein aberrantly expressed on the cell surface of activated malignant and stromal cells in solid tumors. TT1 peptide is after binding to p32 proteolytically cleaved to expose C-terminally the RGAR peptide that interacts with tissue penetration receptor NRP-1. Current preclinical study focused on intraperitoneal (IP) tumors (i.e gastric, colon and ovarian cancer) in exploring new imaging and therapeutic strategies by using different nanoparticles coated with tumor penetrating peptides. Specific focus was on polymeric and iron oxide nanoparticles and their selectivity towards IP tumor lesions following IP administration. We used different IP tumor cell lines and mouse models in animal experimentations. The results from the study show that by conjugating TPP on the surface on nanoparticles the accumulation in the tumor tissue is increased. IP administered TPP-nanoparticles accumulate in the tumor tissue by direct binding as well as indirectly via systemic circulation. Importantly, peptide targeted nanoparticles increased therapeutic efficacy of nanoparticles loaded with anticancer drugs.
Gastrointestinal and gynecological malignancies often disseminate in the peritoneal cavity and cause severe complications such as bowel obstruction and the formation of ascites- a condition known as peritoneal carcinomatosis (PC). PC results from the dissemination of the primary tumor or seeding after surgical intervention and is a cause for incurability of intra-abdominal cancers. In the treatment of peritoneal tumor lesions, intraperitoneal chemotherapy can be used to improve delivery of drugs into peritoneal tumors by providing direct contact and higher local concentration, but this approach as well is not harmless and can cause side effects in the normal organs residing in the IP cavity. IP chemotherapy is an attractive strategy to improve the outcome of PC. During the last decades, substantial amount of work has been put into improving the therapeutic outcome of PC by applying different therapeutic approaches that maximize selectivity and limit side effects. Nanoparticles in the context of direct targeting of IP tumors are actively being evaluated in preclinical studies due to their potential of increasing the retention time in the IP cavity and to target drugs specifically to the tumor site compared to the conventional drugs. A few nanoparticle formulations of chemotherapeutic drugs have reached human trials, but there are no approved drug formulations for the specific use in the IP cavity. Novel strategies such as development of precision nanomedicines to specifically target cancerous lesions and development of drugs/nanoparticles with extended residence time in the IP cavity may help to increase efficacy of IP chemotherapy. The tissue selectivity and efficacy of nanoparticles and chemotherapeutic drugs can be increased by conjugating affinity ligands (i.e antibodies, peptides, aptamers) on their surface. Our lab focuses on tumor penetrating peptides (TPP), such as iRGD and TT1. The iRGD peptide is recruited to integrins expressed on endothelial cells and other cells in tumors. After recruitment to integrins, iRGD is proteolytically cleaved to expose c-terminally CRGDK CendR motif, and the truncated peptide loses most of its integrin-binding capacity and gains affinity for neuropilin-1 (NRP-1). Binding to NRP-1 mediates penetration to cells and tissues. The primary homing receptor for TT1 is p32, a mitochondrial protein aberrantly expressed on the cell surface of activated malignant and stromal cells in solid tumors. TT1 peptide is after binding to p32 proteolytically cleaved to expose C-terminally the RGAR peptide that interacts with tissue penetration receptor NRP-1. Current preclinical study focused on intraperitoneal (IP) tumors (i.e gastric, colon and ovarian cancer) in exploring new imaging and therapeutic strategies by using different nanoparticles coated with tumor penetrating peptides. Specific focus was on polymeric and iron oxide nanoparticles and their selectivity towards IP tumor lesions following IP administration. We used different IP tumor cell lines and mouse models in animal experimentations. The results from the study show that by conjugating TPP on the surface on nanoparticles the accumulation in the tumor tissue is increased. IP administered TPP-nanoparticles accumulate in the tumor tissue by direct binding as well as indirectly via systemic circulation. Importantly, peptide targeted nanoparticles increased therapeutic efficacy of nanoparticles loaded with anticancer drugs.
Description
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Keywords
cancer (medicine), gastrointestinal tumours, ovarian cancer, pharmacotherapy, anticancer drugs, cancer cells, cell-penetrating peptides, nanoparticles, cytotoxity