Deformable Discoidal Polymeric Nanoconstructs for the Precise Delivery of Therapeutic and Imaging Agents
Authors: Anna Lisa Palange, Roberto Palomba, Ilaria F. Rizzuti, Miguel Ferreira, Paolo Decuzzi
Journal: Molecular Therapy (2017)

Over the last 15 years, a plethora of materials and different formulations have been proposed for the realization of nanomedicines. Yet drug-loading efficiency, sequestration by phagocytic cells, and tumor accumulation are sub-optimal. This would imply that radically new design approaches are needed to propel the clinical integration of nanomedicines, overcoming well-accepted clichés. This work briefly reviews the use of deformable discoidal nanoconstructs as a novel delivery strategy for therapeutic and imaging agents. Inspired by blood cell behavior, these nanoconstructs are designed to efficiently navigate the circulatory system, minimize sequestration by phagocytic cells, and recognize the tortuous angiogenic microvasculature of neoplastic masses. This article discusses the notion of nanoparticle margination and vascular adhesion, as well as advantages associated with deformable particles. Finally, details on the synthesis, physico-chemical properties, and in vivo characterization of discoidal polymeric nanoconstructs are provided, with particular emphasis on their ability to independently control size, shape, surface properties, and mechanical stiffness. These nanoconstructs could help in gaining a deeper understanding of the mechanisms regulating the behavior of nanomedicines and identifying optimal delivery strategies for patient-specific therapeutic interventions. Over the last 15 years, a plethora of materials and different formulations have been proposed for the realization of nanomedicines. Yet drug-loading efficiency, sequestration by phagocytic cells, and tumor accumulation are sub-optimal. This would imply that radically new design approaches are needed to propel the clinical integration of nanomedicines, overcoming well-accepted clichés. This work briefly reviews the use of deformable discoidal nanoconstructs as a novel delivery strategy for therapeutic and imaging agents. Inspired by blood cell behavior, these nanoconstructs are designed to efficiently navigate the circulatory system, minimize sequestration by phagocytic cells, and recognize the tortuous angiogenic microvasculature of neoplastic masses. This article discusses the notion of nanoparticle margination and vascular adhesion, as well as advantages associated with deformable particles. Finally, details on the synthesis, physico-chemical properties, and in vivo characterization of discoidal polymeric nanoconstructs are provided, with particular emphasis on their ability to independently control size, shape, surface properties, and mechanical stiffness. These nanoconstructs could help in gaining a deeper understanding of the mechanisms regulating the behavior of nanomedicines and identifying optimal delivery strategies for patient-specific therapeutic interventions. Nanoparticles for the systemic delivery of therapeutic and imaging agents have been demonstrated in pre-clinical studies for the early detection and treatment of cancer1Peer D. Karp J.M. Hong S. Farokhzad O.C. Margalit R. Langer R. Nanocarriers as an emerging platform for cancer therapy.Nat. Nanotechnol. 2007; 2: 751-760Crossref PubMed Scopus (6909) Google Scholar and cardiovascular,2Mulder W.J. Jaffer F.A. Fayad Z.A. Nahrendorf M. Imaging and nanomedicine in inflammatory atherosclerosis.Sci. Transl. Med. 2014; 6: 239sr1Crossref PubMed Scopus (142) Google Scholar neurodegenerative,3Nunes A. Al-Jamal K.T. Kostarelos K. Therapeutics, imaging and toxicity of nanomaterials in the central nervous system.J. Control. 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Trepel M. Lahdenranta J. Cardó-Vila M. Giordano R.J. Mintz P.J. Ardelt P.U. Yao V.J. Vidal C.I. et al.Steps toward mapping the human vasculature by phage display.Nat. Med. 2002; 8: 121-127Crossref PubMed Scopus (499) Google Scholar The proper combination of size and shape is crucial in facilitating nanoparticle adhesion to the tumor microvasculature. For a given volume, discoidal or cylindrical nanoparticles would expose a larger surface of adhesion to vessel walls and simultaneously establish multiple molecular bonds and strong colloidal interactions with endothelial cells, as compared to spherical nanoparticles. Also, adhering discoidal and cylindrical nanoparticles would feel lower hemodynamic dislodging forces. Therefore, for a given nanoparticle volume, the non-spherical shape is pivotal in maximizing vascular adhesive interactions while minimizing dislodging hemodynamic forces, (Figure 2).43Adriani G. de Tullio M.D. Ferrari M. Hussain F. Pascazio G. Liu X. Decuzzi P. The preferential targeting of the diseased microvasculature by disk-like particles.Biomaterials. 2012; 33: 5504-5513Crossref PubMed Scopus (125) Google Scholar, 46Decuzzi P. Pasqualini R. Arap W. Ferrari M. Intravascular delivery of particulate systems: does geometry really matter?.Pharm. Res. 2009; 26: 235-243Crossref PubMed Scopus (510) Google Scholar Furthermore, it should be emphasized here that small discoidal or cylindrical nanoparticles would feel small dislodging hemodynamic forces even in healthy capillaries, where they could readily deposit, leading to undesired, non-specific accumulation. On the other hand, large discoidal or cylindrical nanoparticles would feel large dislodging forces even within the tumor microvasculature, where they would less likely deposit. Consequently, preferential deposition within the tortuous tumor microvasculature is favored for discoidal or cylindrical nanoparticles exhibiting a sub-micrometric to micrometric characteristic size. In recent years, this evidence has led to the development of non-spherical micrometric and sub-micrometric particles for the delivery of drug molecules and contrast agents. Table 1 summarizes some of the features of these nanoparticles. For instance, P.D. has contributed to the design and pre-clinical testing of Ferrari's discoidal mesoporous silicon particles that tend to preferentially deposit within the tumor microvasculature because of a favorable balance between adhesion and margination dynamics.46Decuzzi P. Pasqualini R. Arap W. Ferrari M. Intravascular delivery of particulate systems: does geometry really matter?.Pharm. Res. 2009; 26: 235-243Crossref PubMed Scopus (510) Google Scholar, 47van de Ven A.L. Kim P. Haley O. Fakhoury J.R. Adriani G. Schmulen J. Moloney P. Hussain F. Ferrari M. Liu X. et al.Rapid tumoritropic accumulation of systemically injected plateloid particles and their biodistribution.J. Control. 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Ther. 2008; 16: 1450-1458Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar also documented the advantages of using micrometric particles for targeting the lung microvasculature. More recently, Merkel et al.51Merkel T.J. Chen K. Jones S.W. Pandya A.A. Tian S. Napier M.E. Zamboni W.E. DeSimone J.M. The effect of particle size on the biodistribution of low-modulus hydrogel PRINT particles.J. Control. Release. 2012; 162: 37-44Crossref PubMed Scopus (94) Google Scholar, 52Merkel T.J. Jones S.W. Herlihy K.P. Kersey F.R. Shields A.R. Napier M. Luft J.C. Wu H. Zamboni W.C. Wang A.Z. et al.Using mechanobiological mimicry of red blood cells to extend circulation times of hydrogel microparticles.Proc. Natl. Acad. Sci. USA. 2011; 108: 586-591Crossref PubMed Scopus (428) Google Scholar introduced the notion of mechanobiological mimicry in the fabrication of long-circulating micrometric particles as artificial RBCs. Indeed, the systemic administration of sub-micrometric and micrometric particles raises concerns mostly on the MPS sequestration, occlusion of small capillary beds, difficulty in crossing the fenestrated tumor endothelium, and limited blood longevity. However, these concerns could be addressed by employing deformable particles.Table 1Anti-cancer Non-spherical Nanoparticles: Materials, Size, Shape, Stiffness, Tumor Accumulation, and Circulation Half-Life of Non-Spherical Nanoparticles That Have Been Documented to Have an Effect in Cancer Therapy and ImagingReferenceMaterialSize (μm)ShapeYoung's Modulus (kPa)Tumor (% ID/g)t1/2 (hr)Key et al.53Key J. Palange A.L. Gentile F. Aryal S. Stigliano C. Di Mascolo D. De Rosa E. Cho M. Lee Y. Singh J. Decuzzi P. Soft discoidal polymeric nanoconstructs resist macrophage uptake and enhance vascular targeting in tumors.ACS Nano. 2015; 9: 11628-11641Crossref PubMed Scopus (124) Google Scholarpolymeric1discoidal1–15∼2024van de Ven et al.47van de Ven A.L. Kim P. Haley O. Fakhoury J.R. Adriani G. Schmulen J. Moloney P. Hussain F. Ferrari M. Liu X. et al.Rapid tumoritropic accumulation of systemically injected plateloid particles and their biodistribution.J. Control. Release. 2012; 158: 148-155Crossref PubMed Scopus (152) Google Scholarsilicon0.6–1discoidalrigid5–10NAMerkel et al.51Merkel T.J. Chen K. Jones S.W. Pandya A.A. Tian S. Napier M.E. Zamboni W.E. DeSimone J.M. The effect of particle size on the biodistribution of low-modulus hydrogel PRINT particles.J. Control. Release. 2012; 162: 37-44Crossref PubMed Scopus (94) Google Scholarpolymeric1–10discoidal6.5no tumor30–90Merkel et al.52Merkel T.J. Jones S.W. Herlihy K.P. Kersey F.R. Shields A.R. Napier M. Luft J.C. Wu H. Zamboni W.C. Wang A.Z. et al.Using mechanobiological mimicry of red blood cells to extend circulation times of hydrogel microparticles.Proc. Natl. Acad. Sci. USA. 2011; 108: 586-591Crossref PubMed Scopus (428) Google Scholarpolymeric5–6discoidal8–65no tumor3–90Anselmo and Mitragotri57Anselmo A.C. Mitragotri S. Impact of particle elasticity on particle-based drug delivery systems.Adv. Drug Deliv. Rev. 2017; 108: 51-67Crossref PubMed Scopus (253) Google Scholarpolymeric0.2spherical0.1–3,000no tumor1–4Smith et al.55Smith B.R. Ghosn E.E. Rallapalli H. Prescher J.A. Larson T. Herzenberg L.A. Gambhir S.S. Selective uptake of single-walled carbon nanotubes by circulating monocytes for enhanced tumour delivery.Nat. Nanotechnol. 2014; 9: 481-487Crossref PubMed Scopus (193) Google ScholarSWNT0.1–0.3cylindricalrigid10–15NAID, injected dose; SWNT, single-walled nanotube; t1/2, half-life. Open table in a new tab