iRGD peptide conjugation potentiates intraperitoneal tumor delivery of paclitaxel with polymersomes

Abstract

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.

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

“…A similar pattern was observed in SKOV-3 ovarian tumor tissue, where linTT1-NWs colocalized with blood vessels and macrophages (Fig. 5), suggesting that a combination of direct penetration from the IP cavity and indirect accumulation via systemic circulation drives tumor accumulation of the linTT1-NWs, as was previously observed for iRGD-coupled polymersomes [16]. In the case of CT-26 tumors, we observed particularly extensive colocalization of linTT1-NWs with CD11b-positive macrophages (Fig.…”

“…Our present report on linTT1-mediated targeting of the PC is a sequel to our recently published studies on tumor homing iRGD peptide for the targeting of peritoneal cancer [16,17]. Both iRGD and linTT1 peptides belong to a novel class of tumor-targeting peptides, tumor penetrating peptides, defined by the presence of cryptic R/KXXR/K C- end Rule (CendR) motif (iRGD: C RGDK GPDC, linTT1: A KRGAR STA) that is activated by proteolytic cleavage to enable NRP-1 binding and activation of CendR cell- and tissue penetration pathway [59].…”

“…Tumor homing peptides identified by in vivo phage biopanning screens are particularly well suited for NP targeting, as phages used as scaffolds to display random peptides are biological nanoparticles themselves [15]. A series of recent studies have demonstrated the utility of iRGD, a tumor-penetrating peptide, for improved tumor-specific penetration of intraperitoneal drugs and nanoparticles and for enhanced IP chemotherapy in mice [16,17]. iRGD uses as recruitment receptors αν in- tegrins, cell surface molecules commonly upregulated during angiogenic response and in tumor cells, and subsequently activates the transtissue transport (CendR) pathway described below.…”

Antibiotic-loaded nanoparticles targeted to the site of infection enhance antibacterial efficacy

“…In addition, some antibiotics are often poorly soluble and therefore difficult to administer. 52 Delivery in pSiNPs has mitigated both of these problems, 17, 18, 21, 24, 42 and targeted pSiNPs add further gains by lowering the total dose needed--thus reducing toxic side effects while increasing efficacy of the treatment.…”

Polyethylenimine-functionalized silver nanoparticle-based co-delivery of paclitaxel to induce HepG2 cell apoptosis

“…Paclitaxel (PTX), a chemotherapeutic agent, is widely used against several types of solid tumors besides breast, ovarian, lung, colon, head, neck, and liver cancers. [21][22][23][24][25][26][27] PTX disrupts the tubulin-microtubule equilibrium, which is different from conventional anticancer drugs affecting nucleic acid synthesis to induce cancer cell death. 28,29 It is considered as an appropriate candidate for chemotherapy because PTX at low concentrations can exert antiangiogenic activity.…”