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WIREs Nanomed Nanobiotechnol
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Nanoparticle drug‐delivery systems for peritoneal cancers: a case study of the design, characterization and development of the expansile nanoparticle

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Nanoparticle (NP)‐based drug‐delivery systems are frequently employed to improve the intravenous administration of chemotherapy; however, few reports explore their application as an intraperitoneal therapy. We developed a pH‐responsive expansile nanoparticle (eNP) specifically designed to leverage the intraperitoneal route of administration to treat intraperitoneal malignancies, such as mesothelioma, ovarian, and pancreatic carcinomatoses. This review describes the design, evaluation, and evolution of the eNP technology and, specifically, a Materials‐Based Targeting paradigm that is unique among the many active‐ and passive‐targeting strategies currently employed by NP‐delivery systems. pH‐responsive eNP swelling is responsible for the extended residence at the target tumor site as well as the subsequent improvement in tumoral drug delivery and efficacy observed with paclitaxel‐loaded eNPs (PTX‐eNPs) compared to the standard clinical formulation of paclitaxel, Taxol®. Superior PTX‐eNP efficacy is demonstrated in two different orthotopic models of peritoneal cancer—mesothelioma and ovarian cancer; in a third model—of pancreatic cancer—PTX‐eNPs demonstrated comparable efficacy to Taxol with reduced toxicity. Furthermore, the unique structural and responsive characteristics of eNPs enable them to be used in three additional treatment paradigms, including: treatment of lymphatic metastases in breast cancer; use as a highly fluorescent probe to visually guide the resection of peritoneal implants; and, in a two‐step delivery paradigm for concentrating separately administered NP and drug at a target site. This case study serves as an important example of using the targeted disease‐state's pathophysiology to inform the NP design as well as the method of use of the delivery system. WIREs Nanomed Nanobiotechnol 2017, 9:e1451. doi: 10.1002/wnan.1451 This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Schematic of expansile nanoparticle (eNP)‐mediated drug delivery to peritoneal tumors. eNPs are administered intraperitoneally and localize to tumors via Materials‐Based Targeting. Disruption of intracellular trafficking results in eNP accumulation and delivery of high concentrations of paclitaxel (PTX) to the target cell.
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(a) Schematic of the two‐step paradigm. (b) Paclitaxel (PTX) partitions into swollen expansile nanoparticle (eNPs) from an aqueous sink; partitioning is significantly reduced when the hydrophobicity of the polymer is reduced. (c) The core of swollen eNPs affords a similarly hydrophobic environment compared to ethyl acetate. (d) A pre‐treatment of eNPs significantly increases the intracellular concentration of PTX compared to pre‐treatment with media or poly(lactic‐co‐glycolic) acid nanoparticles (PLGA‐NPs). (e) Pre‐treatment of established intraperitoneal mesothelioma tumors prior to administration of Taxol results in significantly increased (~10‐fold) intratumoral concentrations of PTX compared to pre‐treatment with media (i.e., Taxol alone) or pre‐treatment with PLGA‐NPs. (Reprinted with permission from Ref . Copyright 2016 Nature Publishing Group)
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(a) Rhodamine fluorescence as a function of incorporation into expansile nanoparticle (eNPs) is optimized in the 0.02% and 0.2% formulations. (b) Rhodamine fluorescence as a function of polymer concentration is optimized in the 0.2% formulation. (c) Highly fluorescent rhodamine‐labelled eNPs (HFR‐eNPs) visually identify tumors (orange in UV light) during cytoreductive surgery. (d) Large, small sub‐cm and microscopic sub‐mm tumors labelled with highly fluorescent rhodamine‐labeled eNP (HFR‐eNPs) are visualized post‐resection. (Reprinted with permission from Ref . Copyright 2016 American Chemical Society)
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(a) Rhodamine‐labelled expansile nanoparticle (Rho‐eNPs; red) localize to the sinusoidal spaces within lymph nodes (blue = nuclei). (b) eNPs loaded with a near‐infrared dye (green) and subcutaneously injected into the mammary fat of a pig traffic over 40 cm to the draining lymph node. (c) Confocal microscopy of the sentinel (i.e., draining) lymph node from mice receiving injections of Rho‐eNPs loaded with Oregon Green‐labelled paclitaxel (PTX‐OG) demonstrate co‐localization of PTX and eNP within the lymph node. (d) PTX‐eNPs deliver 10‐fold more PTX to the lymph nodes following a subcutaneous injection in the mammary fat pad than is achieved with Taxol. (e) PTX‐eNPs significantly reduce the incidence of lymphatic disease in an orthotopic model of breast cancer. Taxol does not significantly decrease lymphatic disease compared to the control. (Reprinted with permission from Ref , Copyright 2013 Elsevier B.V.)
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(a) Fluorescent rhodamine‐labelled expansile nanoparticle (Rho‐eNPs; orange in UV light) localize to pancreatic tumors within 1–4 h of intraperitoneal injection. (b) Rho‐eNPs penetrate deep into and entirely throughout some tumors. (c) Paclitaxel‐loaded eNPs (PTX‐eNPs) provide an equivalent survival benefit to Taxol in an orthotopic, cancer stem‐cell‐derived model of pancreatic cancer. PTX‐eNPs show a trend, though not significant, toward reduced tumor burden. (d) PTX‐eNPs demonstrate reduced toxicity, as quantified by duodenal wall thickness and diameter, compared to Taxol. (Reprinted with permission from Ref , Copyright 2016 Future Medicine Ltd.)
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(a) Schematic of the expansile nanoparticle (eNP) and non‐expansile nanoparticle (neNP) chemical structures and function. (b) Hydrolysis of the eNP and neNP protecting groups as a function of time under pH 5 and pH 7.4 conditions. (c) Hydrophobicity of the eNP as a function of time in swelling particles (pH 5) and unswollen particles (pH 7.4). (d–f) Transmission, freeze‐fracture transmission, and scanning electron micrographs of unswollen eNPs at pH 7.4 and swollen eNPs at pH 5. A decrease in eNP density (opacity in d) and increase in eNP size (e, f) are readily apparent. (g) eNP swelling and neNP lack‐of swelling is characterized via dynamic light scattering at pH 5 and 7.4. (h) Particle‐by‐particle swelling of eNPs incubated at pH 5 is observed using scanning ion occlusion sensing (qNano) technology. (Reprinted with permission from Ref . Copyright 2009 American Chemical Society; Ref . Copyright 2013 They Royal Society of Chemistry)
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(a) Paclitaxel‐loaded eNPs (PTX‐eNPs) display equivalent cytotoxicity to Taxol in vitro against OVCAR‐3 breast cancer cells. (b) PTX‐eNPs are significantly (*P < 0.01) more cytotoxic than Taxol in multi‐drug resistant human ovarian cancer cells at concentrations greater than 10 ng/mL. (c) Fluorescent, rhodamine‐labelled‐eNPs (Rho‐eNPs) localize specifically to regions of intraperitoneal ovarian cancer. (d) PTX‐eNPs reduce the incidence of significant tumor recurrence (0%) in an orthotopic model of ovarian cancer compared to Taxol (40% significant recurrence). (Reprinted with permission from Ref . Copyright 2012 Society of Surgical Oncology)
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(a) Pharmacokinetics of paclitaxel (PTX) administered via expansile nanoparticle (eNPs) or as Taxol. Paclitaxel‐loaded eNPs (PTX‐eNPs) deliver 10‐ to 100‐fold more PTX to intraperitoneal mesothelioma tumors than is achieved with Taxol. (b) In a multi‐dose established disease model, PTX‐eNPs significantly improve survival compared to all controls and 33% of animals demonstrate a complete clinical response. (c) Doubling the weekly dose of PTX‐eNPs or Taxol to 20 mg/kg/week does not improve survival compared to the 10 mg/kg/week dose. (d) Doubling the duration of dosing from 4 to 8 weeks increases overall survival of PTX‐eNP‐treated animals while providing no benefit to Taxol‐treated animals. (Reprinted with permission from Ref . Copyright 2013 Elsevier B.V.)
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Materials‐Based Targeting. (a) Confocal microscopy demonstrates that expansile nanoparticle (eNPs) localize to late endosomes/lysosomes in vitro. (b) Pharmacologic inhibition of eNP uptake demonstrates that macropinocytosis is the primary pathway of particle internalization. (c) Schematic of proposed intracellular action of eNPs leading to prolonged tumoral accumulation. (d) Quantification of LC3‐II in MSTO‐211H mesothelioma tumor cells demonstrates dose‐dependent increases when treated with eNPs. (e) Fluorescently labelled eNPs (blue/white) accumulate specifically within regions of intraperitoneal tumor (white dashed circles) and remain for at least 2 weeks. (f) eNP internalization into malignant tumor cells in vitro is an order of magnitude faster than in healthy epithelial cells. (Reprinted with permission from Ref . Copyright 2013 American Chemical Society; Ref . Copyright 2016 Elsevier B.V.)
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Paclitaxel (PTX) release from expansile nanoparticle (eNPs) is characterized by high‐performance liquid chromatography (HPLC) at pH 5 and pH 7.4. eNPs release PTX in a pH‐ and time‐dependent manner. Control non‐expansile nanoparticles (neNPs) and poly(lactic‐co‐glycolic) acid (PLGA)‐NPs exhibit burst release regardless of pH. Control heavily crosslinked‐eNPs (30X‐eNPs) do not exhibit pH‐dependent release. (Reprinted with permission from Ref . Copyright 2009 American Chemical Society; Ref . Copyright 2016 Future Medicine Ltd.)
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