Development of multitargeted tumor penetrating peptides
Kuupäev
2020-12-15
Autorid
Ajakirja pealkiri
Ajakirja ISSN
Köite pealkiri
Kirjastaja
Abstrakt
Kasvajaliste haiguste ravivõimalused on piiratud, kuna süsteemne keemiaravi on madala efektiivsusega ning patsiendile manustatavat ravimidoosi piiravad kõrval- nähud tervetes kudedes. Üheks võimaluseks ravimite ja kontrastainete efektiivsemaks muutmiseks ja kõrvalnähtude vähendamiseks on nende laadimine nano-osakestesse. Nanoosakeste abil on võimalik parandada ravimite lahustuvust, koe- selektiivsust ja vabanemist sihtmärkkoes. Vähiravimite ja nanoosakeste koe- selektiivsuse ja efektiivsuse parandamiseks saab neid suunata keemiliselt konjugeeritud kullerpeptiididega. Kullerpeptiidide kasutamisel kasvajaliste haiguste täppisteraapiaks vajavad tähelepanu kaks olulist probleemi: (1) vereringest ligipääsetavate rakupinna retseptorvalkude limiteeriv kogus, mis seab piirid kasvajakoesse afiinsus-suunatavale ravimikogusele; (2) maliigsete rakkude geneetiline ebastabiilsus, mis võib viia resistentsuse kujunemisele afiinsus-suunatud ravimite suhtes.
Käesolevas töös kirjeldatud prekliinilistes uuringutes töötati välja kullerpeptiidid, mis seonduvad kahe või enama rakuvälise maatriksi vähispetsiifilise vormiga. PL1 (järjestus: PPRRGLIKLKTS) on kaksik-spetsiifiline peptiid, seondub selektiivselt Tenastsiin-C C-isovormiga ning Fibronektiini EDB domääniga. Need mõlemad molekulid on indutseeritud paljudes soliidtuumorites. Teine peptiid, PL3 (järjestus: AGRGRLVR) seondub lisaks Tenastsiin-C C-isovormile neuropiliin-1ga – see interaktsioon käivitab vähispetsiifilise internalisatsiooni ja koepenetratsiooni raja. Käesolevas töös näidati, et võrreldes tavapäraste ühe molekulaarse märklauaga seonduvate peptiididega tagavad multispetsiilised peptiidid terapeutiliste ja diagnostiliste nanoosakeste parema akumuleerumise hiirtes modelleeritud soliidtuumorites. Töös näidati, et kullerpeptiididega suunamine parandab raudoksiidi nanoosakeste kontrasti kasvajakoe elupuhusel kuvamisel magnetresonantstomograafia abil. Eksperimentaalteraapia hiiremudelil näitas, et toksiliste nanoosakeste suunamine vähiselektiivsete peptiididega võimendas osakeste vähivastast toimet.
Töö tulemusi on tulevikus võimalik rakendada kliinilistes uuringutes, et leida võimalusi kasvajaliste protsesside senisest tundlikumaks diagnostikaks ja efektiivsemaks raviks.
Treatment options for tumors are limited due to the low efficacy of systemic chemotherapy and dose-limiting side effects. One way to improve the efficacy of drugs and contrast agents and to reduce side effects is to load these compounds in nanoparticles. Nanoparticles can be used to improve the solubility, tissue selectivity, and release of the drugs at the target site. For tissue-selective delivery, nanoparticles can be precision-targeted with homing peptides. Two problems need to be considered when using tumor homing peptides: (1) a limiting amount of peptide target receptor proteins that limits the delivery capacity of the system; and (2) genetic instability of malignant cells, which may lead to mutations in the peptide-binding domain of the receptor and development of resistance to affinity-targeted drugs. In preclinical studies described here, targeting peptides were developed that bind to cancer-specific isoforms of extracellular matrix molecules. PL1 (sequence: PPRRGLIKLKTS) is a dual-specific peptide that binds to the C isoform of Tenascin-C and the EDB domain of Fibronectin. Both of these molecules are upregulated in many solid tumors, and a PL1-enabled delivery results in robust and uniform accumulation of nanoparticles in tumor tissue. Another peptide, PL3 (sequence: AGRGRLVR), binds in addition to the C-domain of Tenascin-C to neuropilin-1 and triggers tumor-specific internalization and tissue penetration pathway. Compared to conventional monospecific tumor homing peptides, multispecific peptides identified here provide a better accumulation of therapeutic and diagnostic nanoparticles in solid tumors modeled in mice. The novel peptides improved the contrast of iron oxide nanoparticles in in vivo detection of tumor tissue by magnetic resonance imaging. Importantly, experimental therapy with peptide-guided pro-apoptotic nanoparticles significantly increased their therapeutic efficacy. These preclinical results warrant downstream clinical studies on development of peptide-guided drugs and imaging agents.
Treatment options for tumors are limited due to the low efficacy of systemic chemotherapy and dose-limiting side effects. One way to improve the efficacy of drugs and contrast agents and to reduce side effects is to load these compounds in nanoparticles. Nanoparticles can be used to improve the solubility, tissue selectivity, and release of the drugs at the target site. For tissue-selective delivery, nanoparticles can be precision-targeted with homing peptides. Two problems need to be considered when using tumor homing peptides: (1) a limiting amount of peptide target receptor proteins that limits the delivery capacity of the system; and (2) genetic instability of malignant cells, which may lead to mutations in the peptide-binding domain of the receptor and development of resistance to affinity-targeted drugs. In preclinical studies described here, targeting peptides were developed that bind to cancer-specific isoforms of extracellular matrix molecules. PL1 (sequence: PPRRGLIKLKTS) is a dual-specific peptide that binds to the C isoform of Tenascin-C and the EDB domain of Fibronectin. Both of these molecules are upregulated in many solid tumors, and a PL1-enabled delivery results in robust and uniform accumulation of nanoparticles in tumor tissue. Another peptide, PL3 (sequence: AGRGRLVR), binds in addition to the C-domain of Tenascin-C to neuropilin-1 and triggers tumor-specific internalization and tissue penetration pathway. Compared to conventional monospecific tumor homing peptides, multispecific peptides identified here provide a better accumulation of therapeutic and diagnostic nanoparticles in solid tumors modeled in mice. The novel peptides improved the contrast of iron oxide nanoparticles in in vivo detection of tumor tissue by magnetic resonance imaging. Importantly, experimental therapy with peptide-guided pro-apoptotic nanoparticles significantly increased their therapeutic efficacy. These preclinical results warrant downstream clinical studies on development of peptide-guided drugs and imaging agents.
Kirjeldus
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Märksõnad
tumor cells, anticancer drugs, cell-penetrating peptides, penetration, extracellular matrix, tenascin, nanomedicine