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Treatment and Therapy

These dendritic cells are then presented with the nano-vaccines (as shown in this image), which are porous silicon particle discs loaded with immune stimulating molecules and tumor antigens. These now activated cells are then injected back into the host to stimulate an anti-tumor response.

Credit: National Cancer Institute

Cancer therapies are currently limited to surgery, radiation, and chemotherapy. All three methods risk damage to normal tissues or incomplete eradication of the cancer. Nanotechnology offers the means to target chemotherapies directly and selectively to cancerous cells and neoplasms, guide in surgical resection of tumors, and enhance the therapeutic efficacy of radiation-based and other current treatment modalities. All of this can add up to a decreased risk to the patient and an increased probability of survival.

Research on nanotechnology cancer therapy extends beyond drug delivery into the creation of new therapeutics available only through use of nanomaterial properties. Although small compared to cells, nanoparticles are large enough to encapsulate many small molecule compounds, which can be of multiple types. At the same time, the relatively large surface area of nanoparticle can be functionalized with ligands, including small molecules, DNA or RNA strands, peptides, aptamers or antibodies. These ligands can be used for therapeutic effect or to direct nanoparticle fate in vivo. These properties enable combination drug delivery, multi-modality treatment and combined therapeutic and diagnostic, known as “theranostic,” action. The physical properties of nanoparticles, such as energy absorption and re-radiation, can also be used to disrupt diseased tissue, as in laser ablation and hyperthermia applications.

Integrated development of innovative nanoparticle packages and active pharmaceutical ingredients will also enable exploration of a wider repertoire of active ingredients, no longer confined to those with acceptable pharmokinetic or biocompatibility behavior. In addition, immunogenic cargo and surface coatings are being investigated as both adjuvants to nanoparticle-mediated and traditional radio- and chemotherapy as well as stand-alone therapies. Innovative strategies include the design of nanoparticles as artificial antigen presenting cells and in vivo depots of immunostimulatory factors that exploit nanostructured architecture for sustained anti-tumor activity.

Delivering Chemotherapy

The traditional use of nanotechnology in cancer therapeutics has been to improve the pharmacokinetics and reduce the systemic toxicities of chemotherapies through the selective targeting and delivery of these anticancer drugs to tumor tissues. The advantage of nanosized carriers is that they can increase the delivered drug’s overall therapeutic index through nanoformulations in with chemotherapeutics are either encapsulated or conjugated to the surfaces of nanoparticles. This capability is largely due to their tunable size and surface properties. Size is a major factor in the delivery of nanotechnology-based therapeutics to tumor tissues. Selective delivery of nanotherapeutic platforms depends primarily on the passive targeting of tumors through the enhanced permeability and retention (EPR) effect. This phenomenon relies on defects specific to tumor microenvironment such as defects in lymphatic drainage, along with increased tumor vasculature permeability, to allow nanoparticles (<200 nm) to accumulate in the tumor microenvironment. Furthermore, the timing or site of drug release can be controlled by triggered events, such as ultrasound, pH, heat, or by material composition.

Several members of the Alliance are working towards developing nanomaterial-based delivery platforms that will reduce the toxicity of chemotherapeutics and increase their overall effectiveness. In the Centers for Cancer Nanotechnology Excellence, the Center for Multiple Myeloma Nanotherapy at Washington University is developing a strategy for photodynamic therapy, which would bypass the toxicity that currently limits the effectiveness of chemotherapy for multiple myeloma patients. This strategy is designed for use in bone marrow, which is normally inaccessible to external radiation sources.

The Innovative Research in Cancer Nanotechnology awardees are focused on understanding the fundamental aspects of nanomaterial interactions with the biological system to improve on the development of cancer therapeutics and diagnostics. Several of these awardees are studying nanoparticle-based delivery and have proposed nanosystems that deliver chemotherapeutics by penetrating through physiological barriers for access to more restricted tumors via targeting and/or mechanical deformation of particles (Yang, Karathanasis, Kabanov). One of them is dedicated to using a synergistic approach for the delivery of paclitaxel and gemcitabine chemotherapeutics in mesoporous silica nanoconstructs (Nel).

Nano-enabled Immunotherapy

Immunotherapy is a promising new front in cancer treatment encompassing a number of approaches, including checkpoint inhibition and cellular therapies. Although results for some patients have been spectacular, only a minority of patients being treated for just a subset of cancers experience durable responses to these therapies. Expanding the benefits of immunotherapy requires a greater understanding of tumor-host immune system interactions. New technologies for molecular and functional analysis of single cells are being used to interrogate tumor and immune cells and elucidate molecular indicators and functional immune responses to therapy. To this end, nano-enabled devices and materials are being leveraged to sort, image, and characterize T cells in the Alliance’s NanoSystems Biology Cancer Center.

This scanning electron microscope image shows dendritic cells, pseudo-colored in green, interacting with T cells, pseudo-colored in pink. The dendritic cells internalize the particles, process the antigens, and present peptides to T cells to direct immune responses.

Credit: National Cancer Institute

Nanotechnologies are also being investigated to deliver immunotherapy. This includes use of nanoparticles for delivery of immunostimulatory or immunomodulatory molecules in combination with chemo- or radiotherapy or as adjuvants to other immunotherapies. Standalone nanoparticle vaccines are also being designed to raise sufficient T cell response to eradicate tumors, through co-delivery of antigen and adjuvant, the inclusion of multiple antigens to stimulate multiple dendritic cell targets, and continuous release of antigens for prolonged immune stimulation. Molecular blockers of immune-suppressive factors produced can also be co-encapsulated in nanoparticle vaccines to alter the immune context of tumors and improve response, an approach being pursued in the Nano Approaches to Modulate Host Cell Response for Cancer Therapy Center at UNC. Researchers in this Center are also investigating the use of nanoparticles to capture antigens from tumors following radiotherapy to create patient specific treatments, similar in principle to a “dendritic cell activating scaffold” currently in a Phase I clinical trial.

Additional uses of nanotechnology for immunotherapy include immune depots placed in or near tumors for in situ vaccination and artificial antigen presenting cells. These and other approaches will advance and be refined as our understanding of cancer immunotherapy deepens.

Depiction of the complex pathway involved in cancer immunotherapy. Nanoparticle delivery vehicles can play a role at multiple points along this pathway.

Credit: National Cancer Institute

Delivering or Augmenting Radiotherapy

Roughly half of all cancer patients receive some form of radiation therapy over the course of their treatment. Radiation therapy uses high-energy radiation to shrink tumors and kill cancer cells. Radiation therapy kills cancer cells by damaging their DNA inducing cellular apoptosis. Radiation therapy can either damage DNA directly or create charged particles (atoms with an odd or unpaired number of electrons) within the cells that can in turn damage the DNA. Most types of radiation used for cancer treatment utilize X-rays, gamma rays, and charged particles. As such, they are inherently toxic to all cells, not just cancer cells, and are given in doses that are as efficacious as possible while not being too harmful to the body or fatal. Because of this tradeoff between efficacy and safety relative to tumor type, location, and stage, often the efficacy of treatment must remain at reduced levels in order to not be overtly toxic to surrounding tissue or organs near the tumor mass.

Nanotechnology-specific research has been focusing on radiotherapy as a treatment modality that could greatly benefit from nanoscale materials’ properties and increased tumor accumulation. The primary mechanisms by which these nanoscale platforms rely are either enhancement of the effect of the radiotherapy, augmentation of the therapy, and/or novel externally applied electromagnetic radiation modalities. More specifically, most of these nanotechnology platforms rely on the interaction between X-rays and nanoparticles due to inherent atomic level properties of the materials used. These include high-Z atomic number nanoparticles that enhance the Compton and photoelectric effects of conventional radiation therapy. In essence, increasing efficacy while maintaining the current radiotherapy dosage and its subsequent toxicity to the surrounding tissue. Other platforms utilize X-ray triggered drug-releasing nanoparticles that deliver drug locally at tumor site or to sensitize the cancer cells to radiotherapy in combination with the drug.

Another type of therapy that relies upon external electromagnetic radiation is photodynamic therapy (PDT). It is an effective anticancer procedure for superficial tumor that relies on tumor localization of a photosensitizer followed by light activation to generate cytotoxic reactive oxygen species (ROS). Several nanomaterials platforms are being researched to this end. Often made of a lanthanide- or hafnium-doped high-Z core, once injected these can be externally irradiated by X-rays allowing the nanoparticle core to emit the visible light photons locally at the tumor site. Emission of photons from the particles subsequently activate a nanoparticle-bound or local photosensitizer to generate singlet oxygen (1O2) ROS for tumor destruction. Furthermore, these nanoparticles can be used as both PDT that generates ROS and for enhanced radiation therapy via the high-Z core. Although many of these platforms are initially being studied in vivo by intratumoral injection for superficial tumor sites, some are being tested for delivery via systemic injection to deep tissue tumors. The primary benefits to the patient would be local delivery of PDT to deep tissue tumor targets, an alternative therapy for cancer cells that have become radiotherapy resistant, and reduction in toxicity (e.g., light sensitivity) common to traditional PDT. Finally, other platforms utilize a form Cherenkov radiation to a similar end, of local photon emission to utilize as a trigger for local PDT. These can be utilized for deep-tissue targets as well.

Delivering Gene Therapy

The value of nanomaterial-based delivery has become apparent for new types of therapeutics such as those using nucleic acids, which are highly unstable in systemic circulation and sensitive to degradation. These include DNA and RNA-based genetic therapeutics such as small interfering RNAs (siRNAs), and microRNAs (miRNAs). Gene silencing therapeutics, siRNAs, have been reported to have significantly extended half-lives when delivered either encapsulated or conjugated to the surface of nanoparticles. These therapeutics are used in many cases to target ‘undruggable’ cancer proteins. Additionally, the increased stability of genetic therapies delivered by nanocarriers, and often combined with controlled release, has been shown to prolong their effects.

Members of the Alliance are exploring nanotechnology-based delivery of nucleic acids as effective treatment strategies for a variety of cancers. In particular, the Nucleic Acid-Based Nanoconstructs for the Treatment of Cancer Center at Northwestern University is focused on the design and characterization of spherical nucleic acids for the delivery of RNA therapeutics to treat brain and prostate cancers. Project 1 of the Nano Approaches to Modulate Host Cell Response for Cancer Therapy Center at UNC-Chapel Hill targets vemurafenib resistant melanoma for direct suppression of drug resistance through delivery of siRNA using their polymetformin nanoparticles. Among the Innovative Research in Cancer Nanotechnology awardees, the Ohio State project (Guo), is focused on systematic characterization of in vitro and in vivo RNA nanoparticle behavior for optimized delivery of siRNA to tumor cells, as well as cancer immunotherapeutics.

Selected References
  1. Matsumura and Maeda, Cancer Res, 1986

  2. Maeda et al., Adv Drug Deliv Rev, 2013

  3. Bertrand et al, Adv Drug Deliv Rev, 2014

  4. Duan et al. Photodynamic Therapy Mediated by Nontoxic Core−Shell Nanoparticles Synergizes with Immune Checkpoint Blockade To Elicit Antitumor Immunity and Antimetastatic Effect on Breast Cancer. JACS 2016

  5. He et al. Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy. Nature Comm. 2016

  6. Giljohann et al., J Am Chem Soc, 2009

  7. Matsumura and Maeda, Cancer Res, 1986

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