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Erschienen in: Annals of Surgical Oncology 1/2020

11.06.2019 | Peritoneal Surface Malignancy

Slippery Nanoparticles as a Diffusion Platform for Mucin Producing Gastrointestinal Tumors

verfasst von: Marian Khalili, MD, Hao Zhou, PhD, Anusha Thadi, MS, Lynsey Daniels, MD, Zhiyuan Fan, PhD, William F. Morano, MD, Joanne Ang, MD, Eve Goldstein, BS, Boris Polyak, PhD, Beth C. Mapow, DO, Hao Cheng, PhD, Wilbur B. Bowne, MD

Erschienen in: Annals of Surgical Oncology | Ausgabe 1/2020

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Abstract

Background

Treatment failure in pseudomyxoma peritonei (PMP) is partly attributed to the ineffective delivery of therapeutics through dense mucinous tumor barriers. We modified the surface of Poly (lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG-NPs) with a low-density, second PEG layer (PLGA-TPEG-NPs-20) to reduce their binding affinity to proteins and improve diffusion through mucin.

Methods

Nanoprecipitation was used to fabricate PLGA-PEG-NPs. To construct the second PEG layer of PLGA-TPEG-NPs-20, PEG-Thiol was conjugated to PLGA-PEG-NPs composed of 80% methoxy PLGA-PEG and 20% of PLGA-PEG-Maleimide. DiD-labeled nanoparticles (NPs) were added to the inner well of a trans-well system containing cultured LS174T or human PMP tissue. Diffusion of NPs was measured via fluorescence signal in the bottom well. In an ex vivo rat model, small intestine was treated with DiD-labeled NPs. In an in vivo murine LS174T subcutaneous tumor model, Nu/Nu nude mice received supratumoral injections (subcutaneous injection above the tumor) of DiD-labeled NPs. Thirty minutes after injection, mice were sacrificed, and tumors were collected. All tissue was cryosectioned, mounted with DAPI-containing media, and inspected via confocal microscopy.

Results

Diffusion profiles of NPs through PMP and cultured LS174T cells were generated. PLGA-TPEG-NPs-20 diffused faster with ~ 100% penetration versus PLGA-PEG-NPs with ~ 40% penetration after 8 h. Increased diffusion of PLGA-TPEG-NPs-20 was further observed in ex vivo rat small intestine as evidenced by elevated luminal NP fluorescence signal on the luminal surface. Subcutaneous LS174T tumors treated with PLGA-TPEG-NPs-20 demonstrated greater diffusion of NPs, showing homogenous fluorescence signal throughout the tumor.

Conclusions

PLGA-TPEG-NPs-20 can be an effective mucin penetrating drug delivery system.
Literatur
1.
Zurück zum Zitat Kawamura H, Kondo Y, Osawa S, et al. A clinicopathologic study of mucinous adenocarcinoma of the stomach. Gastric Cancer. 2001;4(2):83–6.PubMedCrossRef Kawamura H, Kondo Y, Osawa S, et al. A clinicopathologic study of mucinous adenocarcinoma of the stomach. Gastric Cancer. 2001;4(2):83–6.PubMedCrossRef
2.
Zurück zum Zitat Sugarbaker PH. Surgical treatment of peritoneal carcinomatosis: 1988 Du Pont lecture. Canadian J Surg. 1989;32(3):164–70. Sugarbaker PH. Surgical treatment of peritoneal carcinomatosis: 1988 Du Pont lecture. Canadian J Surg. 1989;32(3):164–70.
3.
Zurück zum Zitat Chua TC, Moran BJ, Sugarbaker PH, et al. Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin Oncol. 2012;30(20):2449–56.CrossRef Chua TC, Moran BJ, Sugarbaker PH, et al. Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin Oncol. 2012;30(20):2449–56.CrossRef
4.
Zurück zum Zitat Ensign LM, Tang BC, Wang YY, et al. Mucus-penetrating nanoparticles for vaginal drug delivery protect against herpes simplex virus. Sci Translational Med. 2012;4(138):138ra179.PubMedCrossRef Ensign LM, Tang BC, Wang YY, et al. Mucus-penetrating nanoparticles for vaginal drug delivery protect against herpes simplex virus. Sci Translational Med. 2012;4(138):138ra179.PubMedCrossRef
5.
Zurück zum Zitat Lai SK, Wang YY, Hanes J. Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues. Adv Drug Delivery Rev. 2009;61(2):158–71.CrossRef Lai SK, Wang YY, Hanes J. Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues. Adv Drug Delivery Rev. 2009;61(2):158–71.CrossRef
6.
Zurück zum Zitat Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R. Nanocarriers as an emerging platform for cancer therapy. Nat Nanotech. 2007;2(12):751–60.CrossRef Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R. Nanocarriers as an emerging platform for cancer therapy. Nat Nanotech. 2007;2(12):751–60.CrossRef
7.
Zurück zum Zitat Brigger I, Dubernet C, Couvreur P. Nanoparticles in cancer therapy and diagnosis. Adv Drug Delivery Rev. 2002;54(5):631–51.CrossRef Brigger I, Dubernet C, Couvreur P. Nanoparticles in cancer therapy and diagnosis. Adv Drug Delivery Rev. 2002;54(5):631–51.CrossRef
8.
Zurück zum Zitat Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986;46(12 Pt 1):6387–92.PubMed Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986;46(12 Pt 1):6387–92.PubMed
9.
Zurück zum Zitat Kratz F, Warnecke A. Finding the optimal balance: challenges of improving conventional cancer chemotherapy using suitable combinations with nano-sized drug delivery systems. J Controlled Release. 2012;164(2):221–35.CrossRef Kratz F, Warnecke A. Finding the optimal balance: challenges of improving conventional cancer chemotherapy using suitable combinations with nano-sized drug delivery systems. J Controlled Release. 2012;164(2):221–35.CrossRef
10.
Zurück zum Zitat Chauhan VP, Stylianopoulos T, Boucher Y, Jain RK. Delivery of molecular and nanoscale medicine to tumors: transport barriers and strategies. Ann Rev Chem Biomolec Eng. 2011;2:281–98.CrossRef Chauhan VP, Stylianopoulos T, Boucher Y, Jain RK. Delivery of molecular and nanoscale medicine to tumors: transport barriers and strategies. Ann Rev Chem Biomolec Eng. 2011;2:281–98.CrossRef
11.
Zurück zum Zitat Zhou H, Fan Z, Deng J, et al. Hyaluronidase embedded in nanocarrier PEG shell for enhanced tumor penetration and highly efficient antitumor efficacy. Nano Lett. 2016;16(5):3268–77.PubMedCrossRef Zhou H, Fan Z, Deng J, et al. Hyaluronidase embedded in nanocarrier PEG shell for enhanced tumor penetration and highly efficient antitumor efficacy. Nano Lett. 2016;16(5):3268–77.PubMedCrossRef
13.
Zurück zum Zitat Chen F, Wang G, Griffin JI, et al. Complement proteins bind to nanoparticle protein corona and undergo dynamic exchange in vivo. Nat Nanotech. 2017;12(4):387–93.CrossRef Chen F, Wang G, Griffin JI, et al. Complement proteins bind to nanoparticle protein corona and undergo dynamic exchange in vivo. Nat Nanotech. 2017;12(4):387–93.CrossRef
14.
Zurück zum Zitat Owens DE, 3rd, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006;307(1):93–102.PubMedCrossRef Owens DE, 3rd, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006;307(1):93–102.PubMedCrossRef
15.
Zurück zum Zitat Zhou H, Fan Z, Li PY, et al. Dense and dynamic polyethylene glycol shells cloak nanoparticles from uptake by liver endothelial cells for long blood circulation. ACS Nano. 2018;12(10):10130–41.PubMedPubMedCentralCrossRef Zhou H, Fan Z, Li PY, et al. Dense and dynamic polyethylene glycol shells cloak nanoparticles from uptake by liver endothelial cells for long blood circulation. ACS Nano. 2018;12(10):10130–41.PubMedPubMedCentralCrossRef
16.
Zurück zum Zitat Popov AE, Bourassa J, Gardner CR, et al. Inventor; Kala Pharmaceuticals, Inc. (Waltham, MA), The Johns Hopkins University (Baltimore, MD), assignee. Nanocrystals, composition, and methods that aid particle transport in mucus. 2013. Popov AE, Bourassa J, Gardner CR, et al. Inventor; Kala Pharmaceuticals, Inc. (Waltham, MA), The Johns Hopkins University (Baltimore, MD), assignee. Nanocrystals, composition, and methods that aid particle transport in mucus. 2013.
17.
Zurück zum Zitat Tang BC, Dawson M, Lai SK, et al. Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier. Proc Natl Acad Sci U S A. 2009;106(46):19268-73.PubMedPubMedCentralCrossRef Tang BC, Dawson M, Lai SK, et al. Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier. Proc Natl Acad Sci U S A. 2009;106(46):19268-73.PubMedPubMedCentralCrossRef
18.
Zurück zum Zitat Grießinger J, Dünnhaupt S, Cattoz B, et al. Methods to determine the interactions of micro- and nanoparticles with mucus. Eur J Pharm Biopharm. 2015;96:464–76.PubMedCrossRef Grießinger J, Dünnhaupt S, Cattoz B, et al. Methods to determine the interactions of micro- and nanoparticles with mucus. Eur J Pharm Biopharm. 2015;96:464–76.PubMedCrossRef
19.
Zurück zum Zitat Friedl H, Dunnhaupt S, Hintzen F, et al. Development and evaluation of a novel mucus diffusion test system approved by self-nanoemulsifying drug delivery systems. J Pharm Sci. 2013;102(12):4406–13.PubMedCrossRef Friedl H, Dunnhaupt S, Hintzen F, et al. Development and evaluation of a novel mucus diffusion test system approved by self-nanoemulsifying drug delivery systems. J Pharm Sci. 2013;102(12):4406–13.PubMedCrossRef
20.
Zurück zum Zitat Choudry HA, O’Malley ME, Guo ZS, Zeh HJ, Bartlett DL. Mucin as a therapeutic target in pseudomyxoma peritonei. J Surg Oncol. 2012;106(7):911–7.PubMedCrossRef Choudry HA, O’Malley ME, Guo ZS, Zeh HJ, Bartlett DL. Mucin as a therapeutic target in pseudomyxoma peritonei. J Surg Oncol. 2012;106(7):911–7.PubMedCrossRef
21.
Zurück zum Zitat Hollingsworth MA, Swanson BJ. Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer. 2004;4(1):45–60.PubMedCrossRef Hollingsworth MA, Swanson BJ. Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer. 2004;4(1):45–60.PubMedCrossRef
22.
Zurück zum Zitat Dilly AK, Lee YJ, Zeh HJ, Guo ZS, Bartlett DL, Choudry HA. Targeting hypoxia-mediated mucin 2 production as a therapeutic strategy for mucinous tumors. Translational Res. 2016;169:19–30.e11. Dilly AK, Lee YJ, Zeh HJ, Guo ZS, Bartlett DL, Choudry HA. Targeting hypoxia-mediated mucin 2 production as a therapeutic strategy for mucinous tumors. Translational Res. 2016;169:19–30.e11.
23.
Zurück zum Zitat Amini A, Masoumi-Moghaddam S, Ehteda A, Morris DL. Secreted mucins in pseudomyxoma peritonei: pathophysiological significance and potential therapeutic prospects. Orphanet J Rare Dis. 2014;9:71.PubMedPubMedCentralCrossRef Amini A, Masoumi-Moghaddam S, Ehteda A, Morris DL. Secreted mucins in pseudomyxoma peritonei: pathophysiological significance and potential therapeutic prospects. Orphanet J Rare Dis. 2014;9:71.PubMedPubMedCentralCrossRef
24.
Zurück zum Zitat Choudry HA, Mavanur A, O’Malley ME, Zeh HJ, Guo Z, Bartlett DL. Chronic anti-inflammatory drug therapy inhibits gel-forming mucin production in a murine xenograft model of human pseudomyxoma peritonei. Ann Surg Oncol. 2012;19(5):1402–9.PubMedPubMedCentralCrossRef Choudry HA, Mavanur A, O’Malley ME, Zeh HJ, Guo Z, Bartlett DL. Chronic anti-inflammatory drug therapy inhibits gel-forming mucin production in a murine xenograft model of human pseudomyxoma peritonei. Ann Surg Oncol. 2012;19(5):1402–9.PubMedPubMedCentralCrossRef
25.
Zurück zum Zitat Leal J, Smyth HDC, Ghosh D. Physicochemical properties of mucus and their impact on transmucosal drug delivery. Int J Pharm. 2017;532(1):555–72.PubMedPubMedCentralCrossRef Leal J, Smyth HDC, Ghosh D. Physicochemical properties of mucus and their impact on transmucosal drug delivery. Int J Pharm. 2017;532(1):555–72.PubMedPubMedCentralCrossRef
26.
Zurück zum Zitat Kalra AV, Campbell RB. Mucin impedes cytotoxic effect of 5-FU against growth of human pancreatic cancer cells: overcoming cellular barriers for therapeutic gain. Br J Cancer. 2007;97(7):910–8.PubMedPubMedCentralCrossRef Kalra AV, Campbell RB. Mucin impedes cytotoxic effect of 5-FU against growth of human pancreatic cancer cells: overcoming cellular barriers for therapeutic gain. Br J Cancer. 2007;97(7):910–8.PubMedPubMedCentralCrossRef
27.
Zurück zum Zitat Kalra AV, Campbell RB. Mucin overexpression limits the effectiveness of 5-FU by reducing intracellular drug uptake and antineoplastic drug effects in pancreatic tumours. Eur Cancer (Oxford, Engl 1990). 2009;45(1):164–73.PubMedCrossRef Kalra AV, Campbell RB. Mucin overexpression limits the effectiveness of 5-FU by reducing intracellular drug uptake and antineoplastic drug effects in pancreatic tumours. Eur Cancer (Oxford, Engl 1990). 2009;45(1):164–73.PubMedCrossRef
28.
Zurück zum Zitat Skrypek N, Duchene B, Hebbar M, Leteurtre E, van Seuningen I, Jonckheere N. The MUC4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the Concentrative Nucleoside Transporter family. Oncogene. 2013;32(13):1714–23.PubMedCrossRef Skrypek N, Duchene B, Hebbar M, Leteurtre E, van Seuningen I, Jonckheere N. The MUC4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the Concentrative Nucleoside Transporter family. Oncogene. 2013;32(13):1714–23.PubMedCrossRef
29.
Zurück zum Zitat Trehoux S, Duchene B, Jonckheere N, Van Seuningen I. The MUC1 oncomucin regulates pancreatic cancer cell biological properties and chemoresistance. Implication of p42-44 MAPK, Akt, Bcl-2 and MMP13 pathways. Biochem Biophys Res Comm. 2015;456(3):757–62.PubMedCrossRef Trehoux S, Duchene B, Jonckheere N, Van Seuningen I. The MUC1 oncomucin regulates pancreatic cancer cell biological properties and chemoresistance. Implication of p42-44 MAPK, Akt, Bcl-2 and MMP13 pathways. Biochem Biophys Res Comm. 2015;456(3):757–62.PubMedCrossRef
30.
Zurück zum Zitat Wissniowski TT, Meister S, Hahn EG, Kalden JR, Voll R, Ocker M. Mucin production determines sensitivity to bortezomib and gemcitabine in pancreatic cancer cells. Int J Oncol. 2012;40(5):1581–9.PubMed Wissniowski TT, Meister S, Hahn EG, Kalden JR, Voll R, Ocker M. Mucin production determines sensitivity to bortezomib and gemcitabine in pancreatic cancer cells. Int J Oncol. 2012;40(5):1581–9.PubMed
31.
Zurück zum Zitat Perry JL, Reuter KG, Kai MP, et al. PEGylated PRINT Nanoparticles: The Impact of PEG density on protein binding, macrophage association, biodistribution, and pharmacokinetics. Nano Lett. 2012;12(10):5304–10.PubMedPubMedCentralCrossRef Perry JL, Reuter KG, Kai MP, et al. PEGylated PRINT Nanoparticles: The Impact of PEG density on protein binding, macrophage association, biodistribution, and pharmacokinetics. Nano Lett. 2012;12(10):5304–10.PubMedPubMedCentralCrossRef
32.
Zurück zum Zitat Yang M, Lai SK, Yu T, et al. Nanoparticle penetration of human cervicovaginal mucus: the effect of polyvinyl alcohol. J Controlled Release. 2014;192:202–8.CrossRef Yang M, Lai SK, Yu T, et al. Nanoparticle penetration of human cervicovaginal mucus: the effect of polyvinyl alcohol. J Controlled Release. 2014;192:202–8.CrossRef
Metadaten
Titel
Slippery Nanoparticles as a Diffusion Platform for Mucin Producing Gastrointestinal Tumors
verfasst von
Marian Khalili, MD
Hao Zhou, PhD
Anusha Thadi, MS
Lynsey Daniels, MD
Zhiyuan Fan, PhD
William F. Morano, MD
Joanne Ang, MD
Eve Goldstein, BS
Boris Polyak, PhD
Beth C. Mapow, DO
Hao Cheng, PhD
Wilbur B. Bowne, MD
Publikationsdatum
11.06.2019
Verlag
Springer International Publishing
Erschienen in
Annals of Surgical Oncology / Ausgabe 1/2020
Print ISSN: 1068-9265
Elektronische ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-019-07493-7

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