Nanotechnology Strategies To Advance Outcomes in Clinical Cancer Care

Abstract

Ongoing research into the application of nanotechnology for cancer treatment and diagnosis has demonstrated its advantages within contemporary oncology as well as its intrinsic limitations. The National Cancer Institute publishes the Cancer Nanotechnology Plan every 5 years since 2005. The most recent iteration helped codify the ongoing basic and translational efforts of the field and displayed its breadth with several evolving areas. From merely a technological perspective, this field has seen tremendous growth and success. However, an incomplete understanding of human cancer biology persists relative to the application of nanoscale materials within contemporary oncology. As such, this review presents several evolving areas in cancer nanotechnology in order to identify key clinical and biological challenges that need to be addressed to improve patient outcomes. From this clinical perspective, a sampling of the nano-enabled solutions attempting to overcome barriers faced by traditional therapeutics and diagnostics in the clinical setting are discussed. Finally, a strategic outlook of the future is discussed to highlight the need for next-generation cancer nanotechnology tools designed to address critical gaps in clinical cancer care.

Keywords: Cancer Nanotechnology Plan; National Cancer Institute; alliance; biological barriers; cancer; image-guided surgery; immunotherapy; metastasis; nanotechnology; oncology; radiotherapy.

Figure 1.. Depiction of the complex pathway involved in cancer immunotherapy.

Nanoparticle delivery vehicles can play a role at multiple points along this pathway. Following cancer cell apoptosis, antigens are released (a) enabling antigen presentation (b). Ultimately, this allows for priming and activation of T cells in lymph nodes (c) that are trafficked back to tumor (d) as cytotoxic T cells (CTL). After tumor infiltration (e), recognition of cancer cell antigens by CTLs (f) follows with CTL killing of specific cancer cells (g). The cancer immune response is an ideal case that does not occur to a large degree due to the ever-evolving immune evasion mechanisms of the cancer. The inherent multicomponent cargo capacity of nanoscale delivery platforms enable alternative approaches in cancer immunotherapy to bolster this response, as depicted in the figure. From the right arrow and moving clockwise, nanoparticles can be designed to help to re-train the tumor microenvironment (TME), increase antigen presenting cells and subsequent T-cell activation, improve antigen presentation, and/or allow increased antigen release from cell death via several modalities. Further and/or simultaneous delivery of diagnostics can enable direct measures of T-cell response and more.

Figure 2.. Present and future of NanoOncology Image-guided Surgical Suites.

Preoperative conventional imaging tools are used to screen for disease and inform optically-driven minimally-invasive and open surgical procedures. Clinically available particle platforms are monitored in real-time using portable multichannel camera systems. Representative translational probes and devices for future clinical use are also shown. In the future, the operating surgeon will select suitable probe-device combinations for specific indications, and be provided with structural, functional, and/or molecular-level data regarding tissue status for further treatment management.

Figure 3.. Mapping of Metastatic Lymph Nodes Using a Clinically Translated Hybrid PET-Optical Silica Nanoparticle (C dots).

(A) Schematic illustration of ¹²⁴I-cRGDY-PEG-C dots. (B) 3D-reconstructed maximum intensity projected image (dorsal view) shows uptake of ¹⁸F-FDG in bone but no evident nodal accumulation (asterisks). (C) 3D-reconstructed maximum intensity projected image (dorsal view) of metastatic locoregional nodes (open arrows) and lymphatic channels (curved arrows) within the neck bilaterally following local injection of ¹²⁴I-cRGDY-PEG-C dots about the primary tumor site (not shown). (D, E) Intraoperative SLN mapping with two- channel NIR optical imaging of the exposed nodal basin. Local injection of fluorescent C dots displayed in dual-channel model (D) RGB color (green) and (E) NIR-fluorescent channels (white). (F, G) Draining lymphatics (arrow) distal to the injection site extending toward the node (N). (H) Image of excised SLN in the NIR channel. (I) Low power view of H&E stained SLN shows a cluster of pigmented cells (black box) (bar=1 mm). (J) Higher magnification of (I) reveals rounded pigmented melanoma cells and melanophages (bar=50 μm). (K) HMB45-stained (red) SLN confirms the presence of metastases (black box, bar = 500 μm). (h) Higher magnification reveals HMB-45+ expressing melanoma cells (bar = 100 μm). Figure adapted with permission from ref . Copyright 2013 RSC Publishing.

Figure 4.. In vivo self-assembling nanoparticle strategy for cancer imaging.

(A) Illustration of a TESLA probe for imaging tumor apoptosis. (B) PET imaging of chemotherapy with C-SNAT; PET/CT images showing HeLa tumor xenografts (white dashed circles) on the right shoulder of mice 60 min after i.v. injection of tracer before and after doxorubicin treatment: (a&b) before treatment, imaged with C-SNAT (211 μCi) after 3D projection (a) and (b) in axial view; (c&d) the same mouse after treatment imaged with C-SNAT (324 μCi) after 3D projection (c) and in axial view (d). All images are normalized to the same scale. T: tumor, H: heart, GB: gall bladder. Figure adapted with permission from ref . Copyright 2014 Macmillan Publishers Ltd.

Figure 5.. Schematic of Drug Delivery Barriers in Solid Tumor.

Effective delivery of therapeutic agents into human tumor cells requires overcoming the following four biological and physical barriers: a) heterogeneous distribution and lack of functional tumor blood vessels in the tumor tissues, b) high interstitial pressure due to proliferation of tumor cells and accumulation of interstitial fluids; c) dense stroma barrier as the results of proliferation and infiltration of tumor associated stromal cells, such as fibroblasts and macrophages, and increased deposition of extracellular matrix; and d) tumor cell membrane barrier and high levels of multi-drug resistant proteins that pump drugs out of cells.

Figure 6.. Transport routes to cross blood–brain barrier (BBB).

A schematic representation of potential mechanisms of biomolecular transport, except cell-mediated transcytosis. In healthy BBB, the tight endothelial junctions restrict small-molecule therapeutics by molecular weight, water solubility, and polarity. Limiting therapy to a small subset of potential drugs that are safe and effective. Transcellular lipophilic transport offers another potential route for lipid soluble therapeutics although they must be able to be delivered through circulation. a&b) Nanoscale platforms have utilized both of these pathways by way of targeting vasculature / local drug accumulation as well as local disruption to enable delivery of co-delivered small-molecule drugs. These platforms have relied on varying degrees of blood-tumor barrier inconsistencies of the tight junctions. c&d) The routes of receptor-mediated and adsorptive transcytosis are often used routes for nano carriers by way of transferrin receptor targeting and other passive mechanisms. e&f) Utilization of transport proteins and efflux pumps are not traditionally used in drug delivery schemes although nano carriers offer the opportunity to utilize additional delivery strategies in the future with these two routes. Figure adapted with permission from ref . Copyright 2011 Elsevier.

Figure 7.. The current understanding of metastasis has evolved greatly over recent years and clinical endpoints are beginning to be reshaped with recent insights.

A) The modern-day view of metastatic dormancy and initiation of secondary outgrowth in metastatic niches. Pre-metastatic seeding with formation of pre-metastatic clusters occurs before tumor cell arrival, which has been shown to be from primary and secondary site communication mechanisms. Once tumor cells arrive they still must compete with the local microenvironment and can exist as asymptomatic dormant micrometastases persisting for years in some examples. Dormancy of these micrometastases are held in check by several mechanisms driven in part by the microenvironment, mass and local angiogenic dynamics. Further driven by cellular dormancy (arrested proliferation and immune-induced), re-establishment at the secondary site will often have been shaped by selection features of the process, ultimately having characteristics of the primary and metastatic sites. Thus, therapeutics require more distinct targets and approaches of relevance to current understanding of metastasis. B) Multiple therapeutic approaches to re-train and/or target the tumor microenvironment are either currently in clinical use or development. The figure displays many of these with respect to route of therapeutic intervention and drug target. Vascular targeting has shown to have limited success at reducing metastatic spread. Many nanotechnology platforms already employ this route for other indications in animal models and this will be an area of need (i) once the drugs prove to have substantial efficacy in human trials. Although, many are targeting the primary lesion, several of these will affect downstream metastatic disease as well (e.g., altering immune cell recruitment and repolarization of developing TME). Furthermore, immune cell tumor recognition has recently been shown to be enhanced greatly and durably from co-delivery of radiotherapy and chemotherapeutics via nanocarriers (ii). These effects are carried downstream towards the nearby lesions and distant metastases. Very few drugs solely target the metastatic lesions to block metastatic seeding and continued growth. Much more emphasis should be placed on nanotechnology co-delivery of chemotherapeutics and inhibitors (iii), such as key cytokine axes (e.g., CCR2, CXCR2/4). Figure adapted with permission from ref . Copyright 2013 Macmillan Publishers Ltd.

Figure 8.. Schematic representation of chemoradiotherapy with small molecule therapeutics (A) or with nanotherapeutics (B).

Axial CT image of patient with rectal cancer is shown. Colored lines represent areas receiving high dose radiotherapy (isodose lines). Small molecule drugs (small red dots) distribute in both tumor as well as normal tissue receiving high dose radiotherapy, thus limiting efficacy and increase toxicity (A). Nanotherapeutics (large red dots) preferentially accumulate in gross tumor, thus improving efficacy and lower toxicity (B).