Nanoparticle/microparticle‐based drug delivery systems for systemic (i.e., intravenous) applications have significant advantages over their nonformulated and free drug counterparts. For example, nanoparticle systems are capable of delivering therapeutics and treating areas of the body that other delivery systems cannot reach. As such, nanoparticle drug delivery and imaging systems are one of the most investigated systems in preclinical and clinical settings. Here, we will highlight the diversity of nanoparticle types, the key advantages these systems have over their free drug counterparts, and discuss their overall potential in influencing clinical care. In particular, we will focus on current clinical trials for nanoparticle formulations that have yet to be clinically approved. Additional emphasis will be on clinically approved nanoparticle systems, both for their currently approved indications and their use in active clinical trials. Finally, we will discuss many of the often overlooked biological, technological, and study design challenges that impact the clinical success of nanoparticle delivery systems.
Nanoparticle/microparticle delivery systems are widely investigated preclinically with many particle‐based formulations and technologies having already been introduced in the clinic.1–5 Oral, local, topical, and systemic (e.g., intravenous) administration are all proven methods that have been Food and Drug Administration (FDA)‐approved for the delivery of nanoparticles/microparticles, depending on the desired application or targeted site. For example: (a) oral delivery of particles has been approved clinically for imaging applications (e.g., Gastromark),6 (b) local delivery of particles has been widely used in the clinic as depot delivery systems for the extended delivery of a variety of biologics including peptides and other small molecules (e.g., DepoCyt),4 (c) topical application of particles has been approved clinically to increase penetration of biologics across the skin barrier (e.g., Estrasorb),7 and (d) systemic delivery of particles has been approved clinically for treating a variety of cancers (e.g., Doxil)8 and other diseases. Given the utility and success of these clinical examples, preclinical research efforts for each of these delivery methods continue to increase with particular attention placed on developing new applications and further improving their delivery and efficacy.
Of these delivery methods, intravenously administered nanoparticles receive the most attention, both preclinically and clinically. The increased interest for intravenous delivery is not surprising given that nanoparticles delivered systemically have direct access to nearly all parts of the body and thus have the most potential to influence clinical care. For this same reason, systemically delivered nanoparticles also face exceedingly difficult challenges with regards to both the delivery aspect (e.g., biological challenges)9, 10 and the regulatory aspect (e.g., study design and approval challenges).11, 12 This review focuses on the clinical translation of intravenously administered nanoparticles, with additional emphasis on the challenges faced by nanoparticles from a clinical and translational point of view. Specifically, the biological, technological, and study design challenges facing the clinical translation of nanoparticles will be discussed. Comprehensive lists of intravenous nanoparticle technologies that are either approved or currently in clinical trials will be provided to highlight the current clinical landscape.
Therapeutic and diagnostic nanoparticles typically fall into two categories: (a) inorganic nanoparticles (e.g., gold, silica, iron oxide, etc.) and (b) organic nanoparticles (e.g., polymeric, liposomes, micelles, etc.). Inorganic nanoparticles have been successful in preclinical studies, are being developed in the clinic for a variety of applications including intraoperative sentinel lymph node imaging and thermal ablation of tumors, and have already been approved for imaging applications and anemia treatment (Figure 1).13–15 Alongside this, organic nanoparticles have also exhibited substantial success in the clinic where they are currently being developed for broad applications ranging from vaccination, to hemostasis, to long‐lasting depot delivery systems, to topical agents for systemic delivery through the skin.1–5 More relevant to this review are nanoparticle formulations that are delivered intravenously, and in this realm, organic nanoparticles predominantly fall into two categories: (a) nanoparticles for gene therapy applications22, 23 or (b) nanoparticles for delivery of small molecule drugs for cancer treatment (e.g., head and neck, melanoma, breast, metastatic, etc.).24, 25 Organic nanoparticle formulations for other applications (e.g., vaccines, fungal treatments, etc.) are also in development and will be highlighted here (Figure 1).
Clinically relevant nanoparticles. Organic and inorganic nanoparticles have been approved for a variety of clinical indications (black text) and are being investigated in current clinical studies for additional indications (red text). Examples included (a) Doxil (200 nm scale bar), (b) Abraxane (200 nm scale bar), (c) CRLX101 (50 nm scale bar), (d) Feraheme (20 nm scale bar), (e) early iteration of Cornell Dots (50 nm scale bar), and (f) gold nanoshells (inset: 100 nm scale bar, main figure: 1,000 nm scale bar) from Nanospectra, makers of AuroLase. (a) Reprinted from ref. . Copyright (2016), with permission from Elsevier. (b) Adapted by permission from Macmillan Publishers Ltd: Nature Communications, copyright (2015). (c) Reprinted from ref. (d) Reprinted from refs. 16 and 19. Copyright (2016), with permission from Elsevier. (e) Adapted with permissions from ref. . Copyright (2012) American Chemical Society. (f) Reprinted from ref.
The main reasons behind the interest in nanoparticle technologies are that: (a) in the case of organic nanoparticles, they possess distinct advantages over many intravenously administered pharmaceuticals and biologics, and (b) in the case of inorganic nanoparticles, many stimuli responsive functions are possible based on specific colloidal assemblies. Organic nanoparticles can be designed and formulated to offer enhanced drug protection, controlled release, extended circulation, and improved targeting to diseased tissues as compared to their free drug counterparts.25, 26 Likewise, inorganic nanoparticles benefit from these same advantages, and additionally from stimuli‐responsive functions arising from their surface plasmon resonance (e.g., thermal heating or imaging) or magnetic responsiveness (e.g., magnetic resonance imaging [MRI] imaging or magnetic targeting) that individual drugs or other molecules (e.g., noncolloidal) do not offer.2, 27 Given these advantages, it has been a long‐held idea that nanoparticles have the potential to dramatically change clinical care by introducing new, or improving upon current, therapies. A large portion of the interest in nanoparticles stems from their potential as a platform delivery system, with the capability of exchanging specific design features (e.g., targeting antibodies, the encapsulated drug, and control over how/when the diseased site interacts with this drug) in a “plug‐and‐play” format to treat additional or other diseases.
Source: Anselmo, Aaron C., and Samir Mitragotri. “Nanoparticles in the clinic.” Bioengineering & translational medicine 1.1 (2016): 10-29.