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      Aerosolization of Nanotherapeutics as a Newly Emerging Treatment Regimen for Peritoneal Carcinomatosis

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          Abstract

          Recent advances in locoregional chemotherapy have opened the door to new approaches for the clinical management of peritoneal carcinomatosis (PC) by facilitating the delivery of anti-neoplastic agents directly to the tumor site, while mitigating adverse effects typically associated with systemic administration. In particular, an innovative intra-abdominal chemotherapeutic approach, known as Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC), was recently introduced to the intraperitoneal (IP) therapy regimens as a palliative therapeutic option in patients with PC, presumably providing a better drug distribution pattern together with deeper drug penetration into tumor nodules within the peritoneal space. Furthermore, the progress of nanotechnology in the past few decades has prompted the application of different nanomaterials in IP cancer therapy, offering new possibilities in this field ranging from an extended retention time to sustained drug release in the peritoneal cavity. This review highlights the progress, challenges, and opportunities in utilizing cancer nanotherapeutics for locoregional drug delivery, with a special emphasis on the aerosolization approach for intraperitoneal therapies.

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          Most cited references91

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          Understanding and controlling the interaction of nanomaterials with proteins in a physiological environment.

          Nanomaterials hold promise as multifunctional diagnostic and therapeutic agents. However, the effective application of nanomaterials is hampered by limited understanding and control over their interactions with complex biological systems. When a nanomaterial enters a physiological environment, it rapidly adsorbs proteins forming what is known as the protein 'corona'. The protein corona alters the size and interfacial composition of a nanomaterial, giving it a biological identity that is distinct from its synthetic identity. The biological identity determines the physiological response including signalling, kinetics, transport, accumulation, and toxicity. The structure and composition of the protein corona depends on the synthetic identity of the nanomaterial (size, shape, and composition), the nature of the physiological environment (blood, interstitial fluid, cell cytoplasm, etc.), and the duration of exposure. In this critical review, we discuss the formation of the protein corona, its structure and composition, and its influence on the physiological response. We also present an 'adsorbome' of 125 plasma proteins that are known to associate with nanomaterials. We further describe how the protein corona is related to the synthetic identity of a nanomaterial, and highlight efforts to control protein-nanomaterial interactions. We conclude by discussing gaps in the understanding of protein-nanomaterial interactions along with strategies to fill them (167 references).
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            Nanoparticle delivery of cancer drugs.

            Nanomedicine, the application of nanotechnology to medicine, enabled the development of nanoparticle therapeutic carriers. These drug carriers are passively targeted to tumors through the enhanced permeability and retention effect, so they are ideally suited for the delivery of chemotherapeutics in cancer treatment. Indeed, advances in nanomedicine have rapidly translated into clinical practice. To date, there are five clinically approved nanoparticle chemotherapeutics for cancer and many more under clinical investigation. In this review, we discuss the various nanoparticle drug delivery platforms and the important concepts involved in nanoparticle drug delivery. We also review the clinical data on the approved nanoparticle therapeutics as well as the nanotherapeutics under clinical investigation.
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              Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner

              The blood vessels of cancerous tumours are leaky 1–3 and poorly organized 4–7 . This can increase the interstitial fluid pressure (IFP) inside tumours and reduce blood supply to them, which impairs drug delivery 8–9 . Anti-angiogenic therapies – which “normalize” the abnormal blood vessels in tumours by making them less leaky – have been shown to improve the delivery and effectiveness of chemotherapeutics with low molecular-weights 10 , but it remains unclear whether normalizing tumour vessels can improve the delivery of nanomedicines. Here we show that repairing the abnormal vessels in mammary tumours, by blocking vascular endothelial growth factor (VEGF) receptor-2, improves the delivery of small nanoparticles (12nm diameter) while hindering the delivery of large nanoparticles (125nm diameter). We utilize a mathematical model to show that reducing vessel wall pore sizes through normalization decreases IFP in tumours, allowing small nanoparticles to enter them more rapidly. However, increased steric and hydrodynamic hindrances, also associated with smaller pores, make it more difficult for large nanoparticles to enter tumours. Our results further suggest that smaller (~12nm) nanomedicines are ideal for cancer therapy, owing to superior tumour penetration.

                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                28 June 2019
                July 2019
                : 11
                : 7
                : 906
                Affiliations
                [1 ]Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, 9000 Ghent, Belgium
                [2 ]Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium
                [3 ]Laboratory of Experimental Surgery, Department of Surgery, Ghent University Hospital, 9000 Ghent, Belgium
                Author notes
                [* ]Correspondence: Stefaan.Desmedt@ 123456UGent.be (S.C.D.S.); Katrien.Remaut@ 123456UGent.be (K.R.); Tel.: +32-9-264-80-76 (S.C.D.S.); +32-9-264-80-46 (K.R.); Fax: +32-9-264-81-89 (S.C.D.S. & K.R.)
                Author information
                https://orcid.org/0000-0001-7692-4419
                Article
                cancers-11-00906
                10.3390/cancers11070906
                6678324
                31261685
                bc69f70a-f2e0-4586-9ea4-fbd72d8deb8f
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 29 April 2019
                : 25 June 2019
                Categories
                Review

                peritoneal carcinomatosis,pipac,nebulization,nanomedicine,localized chemotherapy,intraperitoneal administration

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