Integrating Nanotechnology into Cancer Care - ACS Publications

May 31, 2019 - physiological barriers and to gain access to the affected anatomic sites, (iii) their bioavailability at the disease site, and. (iv) th...
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Integrating Nanotechnology into Cancer Care Piotr Grodzinski,*,† Moritz Kircher,‡ Michael Goldberg,‡ and Alberto Gabizon§ †

National Cancer Institute, National Institutes of Health, Rockville, Maryland 20814, United States Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, United States § Shaare Zedek Medical Center and Hebrew University-School of Medicine, Jerusalem, Israel

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ABSTRACT: Research activity in medical and cancer nanotechnology has grown dramatically over the past 15 years. The field has become a cradle of multidisciplinary investigations bringing together physicists, chemists, and engineers working with clinicians and biologists to address paramount problems in cancer care and treatment. Some have argued that the explosion in the number of research papers has not been followed by sufficient clinical activity in nanomedicine. However, three new nanodrugs have now been approved by the U.S. Food and Drug Administration (FDA) in the past three years, confirming the validity of nanotechnology approaches in cancer. Excitingly, translational pipelines contain several additional intriguing candidates. In this Nano Focus article, we discuss potential barriers inhibiting further incorporation of nanomedicines into patient care, possible strategies to overcome these barriers, and promising new directions in cancer interventions based on nanotechnology. Insights presented herein are outcomes of discussions held at a recent strategic workshop hosted by the National Cancer Institute (NCI), which brought together research, clinical, and commercial leaders of the nanomedicine field. ince the first approval by the U.S. Food and Drug Administration (FDA) of a liposomal nanomedicine (Doxil) for Kaposi sarcoma and ovarian cancer in the 1990s, remarkable progress has been made toward the synthesis and characterization of engineered nanoparticles for the imaging and treatment of cancers.1,2 FDA-approved nanopharmaceuticals (Doxil, Abraxane, Marqibo, Onyvide, Vyxeos, and others) have reduced life-threatening toxicities associated with the active pharmaceutical ingredient (API) and have resulted in modest improvement in the overall survival of patients.3 Despite these advances, clinical applications of nanoparticle-based therapeutic and imaging agents remain limited by biological, immunological, and translational barriers and have not yet met the expectations generated by preclinical results.3 The clinical success of nanoparticles is dependent on (i) their stability and time in circulation, (ii) their ability to cross physiological barriers and to gain access to the affected anatomic sites, (iii) their bioavailability at the disease site, and (iv) their safety profile. Improving these characteristics should contribute to enhanced efficacy of nanomedicines, consequently helping to bring them into mainstream cancer treatment. Progress in particle design can be pursued in concert with modifications of the tumor microenvironment, which can have large effects on particle accumulation. In parallel, the efficacy issue can be tackled by identifying more potent APIs in conjunction with selective and niche cancer interventions where nanoparticle-based delivery provides significant advantages. Finally, engaging both strategies in


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cleverly designed, rigorous clinical trials with patient preselection as an option should lead us to the goal of a substantial improvement in efficacy of nanomedicines.

INNOVATIVE NANOMATERIALSAN OPPORTUNITY FOR IMPROVED EFFICACY The majority of nanoparticle-based treatments that have been approved for clinical use to date involve nominally spherical liposomes.2 Materials scientists, however, have been working on a wide range of nanoparticle designs with core materials possessing various magnetic, optical, and biochemical properties and nanoparticles varying in size, shape, hardness, and surface properties. Changing the aspect ratio of nanoparticles (from spherical to rod-like) modifies cellular uptake, with rods tending to migrate in the bloodstream toward vessel walls4 and consequently be more readily endocytosed. Similarly, the shape of the particles affects biodistribution and the rate of extravasation from circulation.5 The shape can be defined by the particular fabrication process and can also vary with the level of drug loading.6 Deformable (“squashable”) nanoparticles exhibit long circulation times due to their ability to avoid sequestration by phagocytic cells.7 Increasingly, inorganic materials, especially porous silica, have been used for drug delivery as well. Materials’ porosity enables high drug loading8 and multistage delivery,9 as larger silica pores can be loaded with smaller liposomal particles that Received: May 31, 2019


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vary in the literature. A recent survey examining a large body of work published over the past 10 years across a variety of formulations and tumor models showed that, on average, less than 1% of the administered nanoparticle dose reaches the malignant tissue.20 Meta-analysis-based evaluations of nanoparticle pharmacologic performance are overshadowed by lumping together nanoparticles with different compositions, sizes, and physicochemical properties, by the use of tracers in unstable association with the nanocarrier, and by neglecting the impact of particle circulation half-life, which is a parameter of paramount importance in determining tumor localization.21 Furthermore, the data discussed in the paper20 were not normalized by tumor weight, thereby distorting the calculated values and their pharmacological significance. For example, using PEGylated liposomes with stable radioisotope labeling, average tumor uptake values of ∼12% injected dose (ID)/gram in a mouse xenograft tumor model22 and ∼11% ID/kg in cancer patients were demonstrated.23 Moreover, when a concomitant marker of tumor viability or metabolic activity was used, the uptake in viable tumor mass was even greater than the calculation based on whole tumor mass.22 Thus, although EPR is subject to significant variability, we contend that it remains a solid pillar behind the passive targeting of nanoparticles to tumors provided that the formulations used are stable and have a long circulation time. Another factor complicating a generalized analysis of nanoparticle accumulation in tumors is the variable of tumor size. Small tumors generally exhibit greater uptake of nanoparticles per unit of tumor weight. This increased uptake is probably the result of a lower interstitial fluid pressure (IFP) and/or a relatively enriched macrophage environment in small tumors. This tumor-size variable has been neglected in clinical development of nanomedicines but may be of great pharmacologic significance and suggests that more emphasis should be put in testing nanomedicines in the early stage of cancers consisting of small tumors down to the millimetric range. The use of ligands to enable active targeting of nanoparticles to tumor cells has thus far not provided added value, and two clinical attempts to deliver docetaxel and doxorubicin, i.e., prostate-specific membrane antigen (PSMA)-targeted BIND01424 and Her2-targeted MM-302,25 respectively, have not progressed. Active targeting improves intracellular uptake of nanoparticles after they reach the tumor, but its contribution to overall nanoparticle tumor accumulation is limited and depends on tumor size and the level of tumor vascularity.1,26 There is limited intratumoral distribution of nanoparticles due to high tumor IFP, and the dense extracellular matrix suppresses convection flow across the tumor, which is the dominant process of extravascular transport for macromolecules and nanoparticles.27 Indeed, nanoparticles, whether targeted or not, tend to remain predominantly in the perivascular region of tumors, thus reducing the chances of widespread tumor exposure.28

are released within the tumor. A combinatorial design engaging porous particles and lipid bilayers produced “protocells” that exhibited liposome-like long circulation times while enabling high loading with diverse cargo and both therapeutic and imaging applications.10 Entirely new classes of materials were also produced: Lin’s group11 synthesized nanometal−organic frameworks (nMOFs)a class of hybrid materials combining metal ions and bridging ligands into “cube-like” unit cells.12 Such nMOFs are compositionally and structurally diverse, are biodegradable, and can be adapted for numerous cancer applications.12 Tailoring nanoparticle design for specific applications and optimizing pharmacokinetic (PK) parameters will critically affect the ultimate performance of the therapeutic construct. However, there is a long road from demonstration of a novel material in an academic laboratory to producing it in larger quantities with the stable and reproducible properties that are required for moving these materials into the clinic. This process is among the reasons why liposomes still dominate the field of advanced clinical trials in nanomedicine and why virtually all approved nanotherapeutics rely on liposomes.2,13 Still, several advanced material designs mentioned above accomplished the feat of obtaining Investigational New Drug (IND) approvals from the FDA. PRINT particles (Liquidia Technologies) have entered clinical trials for pulmonary arterial hypertension and are being considered for future cancer applications.14 Multistage delivery vectors are being produced under GMP conditions at the Methodist Research Institute (Houston, TX) for metastatic breast cancer therapeutic trials,15 while nMOFs are being developed by RiMO Therapeutics for combination cancer therapies involving radiation and immunotherapy.16 Following these initial examples, it is expected that more complex nanoparticle designs will gradually advance to the clinic, especially in cases where their properties confer a distinct therapeutic advantage over simpler and more established designs, thereby justifying the higher cost and complexity of associated manufacturing processes.Tailoring nanoparticle design for specific applica-

Tailoring nanoparticle design for specific applications and optimizing pharmacokinetic parameters will critically affect the ultimate performance of the therapeutic construct. tions and optimizing pharmacokinetic parameters will critically affect the ultimate performance of the therapeutic construct.

TUMOR ACCUMULATION AND PENETRATION CONSIDERATIONS It is generally agreed that the major obstacle in increasing the efficacy of nanomedicine-based anticancer drugs lies in poor tumor penetration of therapeutic nanoparticles as well as suboptimal balance between drug retention in circulation and drug release at the tumor site.17,18 The physiological barriers include microvessel permeability and intratumoral diffusion. The enhanced permeability and retention (EPR) effect17 is believed to be the main mechanism responsible for nanocarriers’ accumulation in tumors, and recent studies suggest that EPR is a clinically relevant phenomenon.19 However, reports on nanoparticle accumulation levels in different organs

OPENING NEW CANCER APPLICATIONS FOR NANOTECHNOLOGY Nano-Immunotherapy. Although the vast majority of work to date in the realm of cancer nanomedicine has focused on delivery of payloads that act on or detect cancer cells, there is burgeoning interest in deploying nanomedicine to modulate the function of immune cells to improve response rates to immunotherapy.29 B

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stiffness can influence uptake by immune cells, particularly phagocytes. Superparamagnetic iron oxide nanoparticles (SPIONs) and 64Cu-labeled polyglucose nanoparticles can respectively be used to monitor TAMs and inflammation by magnetic resonance imaging (MRI)39 and positron emission tomography (PET).40 Particle-based imaging has utility not only in tracking immune cell populations but also for surgical applications.It is critical that investigators conduct thorough

Indeed, addressing the myeloid compartment is a simple and effective means of applying nanomedicine. Infiltration of monocytes is often a hallmark of aggressive cancers,30 and local differentiation of monocytes into tumor-associated macrophages (TAMs) produces a hypoxia-responsive gene signature, including expression of HIF-2α, which is an independent prognostic factor for poor outcome.31 Thus, the ability to leverage the localization and uptake capabilities of TAMs represents an attractive opportunity for intervention. Nanoparticles are phagocytosed efficiently by TAMs, which play a central role in immune suppression within tumors. This natural phenomenon renders nanoparticles a highly effective tool for reprogramming the tumor microenvironment. Indeed, uptake of particles by TAMs yields a source of “drug reservoirs” that extend the release of the therapeutic payload locally. Although this tactic has been employed effectively to deliver cytotoxic chemotherapy,32 cancer cell-intrinsic approaches are often less durable than engagement of the immune system, which has the capacity for adaptive antitumor memory. The ability to sustain the release of immunotherapy locally is expected not only to delay tumor progression but also to produce curative outcomes. In addition to utilizing TAMs as drug depots, nanoparticles can be loaded with molecules that deplete the TAMs themselves, thereby removing these mediators of immunosuppression. Administration of PEGylated liposomal nanoparticles loaded with alendronate, but not free alendronate, conferred antitumor effects among tumor-bearing mice.33 Notably, TAMs can be polarized from a pro-tumor (“M2”) to an antitumor (“M1”) phenotype, so reprogramming macrophagesrather than depleting them outrightcan be beneficial.34 As an example, Class IIa histone deacetylase (HDAC) inhibitors improve response rates to immune checkpoint blockade35 and concentrating the dose of such small molecules within TAMs should increase the benefit of combination immunotherapy. In addition to local effects on TAMs, nanoparticles are known to interact with other components of the immune system to varying extents. These interactions can affect drug PK parameters and may have significant clinical consequences. Interaction with the complement system may lead to dangerous acute infusion responses.36 The majority of intravenously administered nanoparticles are ultimately cleared by the mononuclear phagocyte system (MPS). Uptake and sequestration of nanoparticles in cells and organs of the MPS are major barriers limiting the circulation half-life and, hence, tumor accumulation of carrier-mediated drugs, but an excessively long circulation half-life also entails risks, as in the case of liposome enhancement of chemotherapy-induced skin toxicity.37 Pharmacokinetics monitoring of nanomedicines could be extremely helpful to individualize dose and schedule when cyclical therapy is advised, as in most treatment protocols. Whereas tumor accumulation is the sole objective for therapies that kill cancer cells directly, immunomodulatory compounds can induce antitumor activity, if they are delivered to secondary lymphoid organs. Thus, it is critical that investigators conduct thorough biodistribution studies at both the organ and cellular levels to enable the determination of structure−activity relationships. Understanding which cells actually take up particles and whether this takes place in the blood, bone marrow, spleen, or lymph nodes is very important.38 Indeed, factors such as size, charge, shape, and

It is critical that investigators conduct thorough biodistribution studies at both the organ and cellular levels to enable the determination of structure− activity relationships.

biodistribution studies at both the organ and cellular levels to enable the determination of structure−activity relationships. Real-Time Surgery Monitoring. In addition to their therapeutic capabilities, nanoparticles also enable effective applications in imaging.41 One of the early examples is ferumoxytol (FMX), an iron oxide nanoparticle that was developed and FDA-approved as an iron replacement for patients with chronic renal failure. This FDA approval has enhanced off-label use of FMX as a magnetic resonance imaging (MRI) contrast agent following much earlier developments of SPIONs for lymph node staging.42 The possibilities of nanomaterials to serve as imaging agents are much wider; however, because they exhibit variable and finely tunable properties adaptable to imaging needs. For example, multiple contrast agents can be incorporated into the same nanoparticle and positioned in different nanoparticle compartments. Such multimodal nanoimaging agents can become powerful by combining the complementary strengths of different imaging techniques. A prime example of this is a combination of a whole-body imaging contrast agent with a high-resolution, high-sensitivity contrast agent leveraging their complementary modalities. One of the earliest reported multimodal imaging approaches was the combination of an ultrasmall SPION with fluorochromes, resulting in an MRI-fluorescent dual-modality imaging agent.43 Multiple different versions of similar MRIfluorescent nanoparticles have since been refined. A more recently developed strategy to combine whole-body imaging with local intraoperative imaging is based on so-called C-dots. These C-dots are small (