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.
Gastrointestinal and gynecological malignancies disseminate in the peritoneal cavity - a condition known as peritoneal carcinomatosis (PC). Intraperitoneal (IP) administration can be used to improve therapeutic index of anticancer drugs used for PC treatment. Activity of IP anticancer drugs can be further potentiated by encapsulation in nanocarriers and/or affinity targeting with tumor-specific affinity ligands, such as tumor homing peptides. Here we evaluated a novel tumor penetrating peptide, linTT1 (AKRGARSTA), as a PC targeting ligand for nanoparticles. We first demonstrated that the primary homing receptor for linTTl, p32 (or gClqR), is expressed on the cell surface of peritoneal carcinoma cell lines of gastric (MKN-45P), ovarian (SKOV-3), and colon (CT-26) origin, and that peritoneal tumors in mice and clinical peritoneal carcinoma explants express p32 protein accessible from the IP space. Iron oxide nanoworms (NWs) functionalized with the linTT1 peptide were taken up and routed to mitochondria in cultured PC cells. NWs functionalized with linTT1 peptide in tandem with a pro-apoptotic [D(KLAKLAK)2] peptide showed p32-dependent cytotoxicity in MKN-45P, SKOV-3, and CT- 26 cells. Upon IP administration in mice bearing MKN-45P, SKOV-3, and CT-26 tumors, linTT1-functionalized NWs showed robust homing and penetration into malignant lesions, whereas only a background accumulation was seen in control tissues. In tumors, the linTT1-NW accumulation was seen predominantly in CD31-positive blood vessels, in LYVE-1-positive lymphatic structures, and in CD11b-positive tumor macrophages. Experimental therapy of mice bearing peritoneal MKN-45P xenografts and CT-26 syngeneic tumors with IP linTT1-D(KLAKLAK)2-NWs resulted in significant reduction of weight of peritoneal tumors and significant decrease in the number of metastatic tumor nodules, whereas treatment with untargeted D(KLAKLAK)2-NWs had no effect. Our data show that targeting of p32 with linTTl tumor-penetrating peptide improves tumor selectivity and antitumor efficacy of IP pro-apoptotic NWs. P32-directed intraperitoneal targeting of other anticancer agents and nanoparticles using peptides and other affinity ligands may represent a general strategy to increase their therapeutic index.
Peritoneal carcinomatosis is present in more than 60% of gastric cancer, 40% of ovarian cancer, and 35% of colon cancer patients. It is the second most common cause of cancer mortality, with a median survival of 1–3 months. Cytoreductive surgery combined with intraperitoneal chemotherapy is the current clinical treatment, but achieving curative drug accumulation and penetration in peritoneal carcinomatosis lesions remains an unresolved challenge. Here we employed flexible and pH-sensitive polymersomes for payload delivery to peritoneal gastric (MKN-45P) and colon (CT26) carcinoma in mice. Polymersomes were loaded with Paclitaxel® and in vitro drug release was studied as a function of pH and time. Paclitaxel-loaded polymersomes remained stable in aqueous solution at neutral pH for up to four months. In cell viability assay on cultured cancer cell lines (MKN-45P, SKOV3, CT26), Paclitaxel-loaded polymersomes were more toxic than free drug or albumin-bound Paclitaxel (Abraxane®). Intraperitoneally administered fluorescent polymersomes accumulated in malignant lesions, and immunofluorescence revealed intense signal inside tumors with no detectable signal in control organs. A dual targeting of tumors was observed: direct (circulation independent) penetration, and systemic, blood vessel-associated accumulation. Finally, we evaluated preclinical antitumor efficacy of polymersomes-paclitaxel in treatment of MKN-45P disseminated gastric carcinoma using a total dose of 7 mg/kg. Experimental therapy with polymersome-Paclitaxel improved the therapeutic index of drug over Paclitaxel-Cremophor and Abraxane®, as evaluated by intraperitoneal tumor burden and number of metastatic nodules. Our findings underline the potential utility of the polymersome platform for delivery of drugs and imaging agents to peritoneal carcinomatosis lesions.
Tumor-selective drug conjugates can potentially improve the prognosis for patients affected by glioblastoma (GBM) -the most common and malignant type of brain cancer with no effective cure.Here we evaluated a novel tumor penetrating peptide that targets cell surface p32, LinTT1 (AKRGARSTA), as a GBM targeting ligand for systemically-administered nanoparticles. LinTT1-functionalization increased tumor homing of iron oxide nanoworms (NWs) across a panel of five GBM models ranging from infiltratively-disseminating to angiogenic phenotypes. LinTT1-NWs homed to CD31-positive tumor blood vessels, including to transdifferentiated endothelial cells, and showed co-localization with tumor macrophages and lymphatic vessels. LinTT1 functionalization also resulted in increased GBM delivery of other types of systemically-administered nanoparticles: silver nanoparticles and albumin-paclitaxel nanoparticles. Finally, LinTT1-guided proapoptotic NWs exerted strong anti-glioma activity in two models of GBM, including doubling the lifespan of the mice in an aggressive orthotopic stem cell-like GBM that recapitulates the histological hallmarks of human GBM. Our study suggests that LinTT1 targeting strategy can be used to increase GBM uptake of systemic nanoparticles for improved imaging and therapy.
Over recent decades multiple therapeutic approaches have been explored for improved management of peritoneally disseminated malignancies—a grim condition known as peritoneal carcinomatosis (PC). Intraperitoneal (IP) administration can be used to achieve elevated local concentration and extended half-life of the drugs in the peritoneal cavity to improve their anticancer efficacy. However, IP-administered chemotherapeutics have a short residence time in the IP space, and are not tumor selective. An increasing body of work suggests that functionalization of drugs and nanoparticles with targeting peptides increases their peritoneal retention and provides a robust and specific tumor binding and penetration that translates into improved therapeutic response. Here we review the progress in affinity targeting of intraperitoneal anticancer compounds, imaging agents and nanoparticles with tumor-homing peptides. We review classes of tumor-homing peptides relevant for PC targeting, payloads for peptide-guided precision delivery, applications for targeted compounds, and the effects of nanoformulation of drugs and imaging agents on affinity-based tumor delivery.
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.
During last decades multiple therapeutic approaches have been explored for improved management of peritoneally disseminated malignancies – a grim condition known as peritoneal carcinomatosis (PC). Intraperitoneal administration can be used to achieve elevated local concentration and extended half-life of the drugs in the peritoneal cavity to improve their anticancer efficacy. However, IP-administered chemotherapeutics have a short residence time in the IP space, and are not tumor selective. An increasing body of work suggests that functionalization of drugs and nanoparticles with targeting peptides increases their peritoneal retention and provides a robust and specific tumor binding and penetration that translates into improved therapeutic response. Here we review a progress in affinity targeting of intraperitoneal anticancer compounds, imaging agents and nanoparticles with tumor homing peptides. We review classes of tumor homing peptides relevant for PC targeting, payloads for peptide-guided precision delivery, applications for targeted compounds and the effects of nanoformulation of drugs and imaging agents on affinity-based tumor delivery.
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