Paclitaxel-Loaded Polymersomes for Enhanced Intraperitoneal Chemotherapy

Abstract

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.

Optimal drug delivery for intraperitoneal paclitaxel (PTX) in murine model

“…It is possible that those nanodrugs in ascitic fluids have a longer retention time in abdomen which enables the efficient penetration in peritoneal nodules. Similar result is shown in PTXpolymersome recently [46].…”

iRGD peptide conjugation potentiates intraperitoneal tumor delivery of paclitaxel with polymersomes

“…Poly(oligoethylene glycol methacrylate)-poly(2-(diisopropylamino)ethyl methacrylate) (P[(OEG) 10 MA] 20 -PDPA 90 ; POEGMA-PDPA) polymersomes are pH-sensitive (Fig. S1): the particles are stable at physiological pH and disassemble under mildly acidic pH due to the protonation of the PDPA block [27,28]. This property of POEGMA-PDPA vesicles renders them well suited for cellular cargo delivery: following cellular internalization, the polymersomes disassemble at endosomal acidic pH followed by endosomal rupture and release of cargo in the cytosol [29–31].…”

“…Thick and robust hydrophobic polymersome membrane is less leaky than lipid bilayer of liposomes [32]. We have demonstrated that the POEGMA-PDPA polymersomes retain the drug inside for several weeks at neutral pH and quickly release the cargo at mildly acidic pH [27]. pH-sensitive polymersomes have been used for intracellular delivery of DNA [29], antibodies [33–35], antibiotics [36], cytotoxic drugs [27,37,38], and peptides [39].…”

Targeting of p32 in peritoneal carcinomatosis with intraperitoneal linTT1 peptide-guided pro-apoptotic nanoparticles

“…IP therapy using mildly heated drug solutions, Hyperthermic IntraPeritoneal Chemotherapy (HIPEC), further enhances drug penetration into malignant tissue, and combining HIPEC with cytoreductive surgery results in improved efficacy of the treatment [6–9]. Encapsulation of cytotoxic drugs in nanoformulations has been also shown to improve the anticancer effect of IP chemotherapy [10]. Even with these improvements, many patients develop recurrent disease [11].…”