Nanomedicine-based intraperitoneal therapy for the treatment of peritoneal carcinomatosis — Mission possible?

Dakwar, George R.; Shariati, Molood; Willaert, Wouter; Ceelen, Wim; Smedt, Stefaan C. De

doi:10.1016/j.addr.2016.07.001

Cited by 80 publications

(76 citation statements)

References 96 publications

(103 reference statements)

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“…Compared to free drugs, IP-administered nanoformulated cancer drugs may have favorable pharmacokinetic and biodistribution profiles [45], and at least 2 nano-therapeutics, Abraxane™ and Nanotax™ are being clinically evaluated in PC clinical trials [46,47]. Our study was designed to evaluate the effect of functionalizing NPs with the p32-binding linTT1 peptide on the tumor targeting and antitumor efficacies of drug-loaded NPs upon IP administration.…”

Section: Discussionmentioning

confidence: 99%

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

Hunt

Simón‐Gracia

Tobi

et al. 2017

Journal of Controlled Release

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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.

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Section: Discussionmentioning

confidence: 99%

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

Hunt

Simón‐Gracia

Tobi

et al. 2017

Journal of Controlled Release

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“…33,34 However, conventional intraperitoneal chemotherapy drugs have a short residence time and require frequent or continuous dosing. How to keep the effective drug concentration to the regional malignancies during the protracted duration of intraperitoneal chemotherapy is challenging.…”

Section: -32mentioning

confidence: 99%

Enhancing the anti-ovarian cancer activity of quercetin using a self-assembling micelle and thermosensitive hydrogel drug delivery system

Wang

et al. 2018

RSC Adv.

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Ovarian cancer, as one of the killers that threaten women's health, has been studied extensively. As a natural bioflavonoid with prospective effects, quercetin is highly recognized for its anti-cancer applications.However, one of the major challenges that quercetin faces is its poor water solubility, instability in physiological media, and subsequent poor bioavailability. Thus, optimizing the ideal drug delivery options is necessary to facilitate the harnessing of the maximum benefits from quercetin. In this study, a quercetin-loaded thermosensitive injectable hydrogel system (Qu-M-hydrogel composites) was constructed based on nanotechnology. Quercetin was encapsulated into MPEG-PCL (with a high drug loading of 7% and minor particle size of 32 nm) and then added into the blank thermosensitive hydrogel Pluronic F-127. The Qu-M-hydrogel composites showed a much slower release than Qu-M in vivo.Moreover, the cytotoxicity, apoptosis induction, and anti-tumor effects of the Qu-M-hydrogel composites on the abdominal SKOV-3 ovarian cancer mouse models were investigated in vivo. Compared with other groups, the Qu-M-hydrogel composites exhibited improved apoptosis induction and cell growth inhibition effects and in vivo trials showed a better balance between the anti-tumor efficacy in the Qu-M-hydrogel composite group than in other groups at an equal drug dose. In conclusion, the prepared Qu-M-hydrogel composites enhanced the anti-tumor activity by providing a high local quercetin concentration, sustained and stable drug release, extended drug retention inside the tumor, and low toxicity to normal tissues. The Qu-M-hydrogel composites might have great potential for clinical application in anti-ovarian cancer activity.

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“…Formulation has a profound effect on the pharmacokinetics, biodistribution, and efficacy of the drugs. As summarized in a recent review by Dakwar et al, nano-and microformulation of nticancer compounds can increase peritoneal retention of drugs that translates into an improved therapeutic efficacy and reduction of the number of IP administrations [17]. As nanoparticles in most cases enter cells via endocytosis, loading of drugs in nanoparticles can also bypass or alleviate drug resistance due to overexpression of drug efflux pumps [18][19][20].…”

Section: Introduction Challenges In Ip Chemotherapymentioning

confidence: 99%

Peritoneal Carcinomatosis Targeting with Tumor Homing Peptides

Simón‐Gracia¹,

Hunt²,

Teesalu³

2018

Preprint

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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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Nanomedicine-based intraperitoneal therapy for the treatment of peritoneal carcinomatosis — Mission possible?

Cited by 80 publications

References 96 publications

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

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

Enhancing the anti-ovarian cancer activity of quercetin using a self-assembling micelle and thermosensitive hydrogel drug delivery system

Peritoneal Carcinomatosis Targeting with Tumor Homing Peptides

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