Nanomedicine in oncology: Tiny particles, huge potential
Click Here to Manage Email Alerts
Nanomedicine has been a promising area of clinical research — particularly in the cancer setting — for decades, and experts said its potential has only increased with advances in cancer diagnostics and therapeutics.
Defined by Tinkle and colleagues as “the use of nanomaterials for diagnosis, monitoring, control, prevention and treatment of disease,” nanomedicine gained wider attention during the past 2 years for its role in combating the global COVID-19 pandemic.
Source: The University of Texas MD Anderson Cancer Center.
“Both Pfizer-BioNTech and Moderna COVID vaccines rely on lipid nanoparticles for delivery of messenger RNA,” Piotr Grodzinski, PhD, chief of NCI’s Nanodelivery Systems and Devices branch, told Healio | HemOnc Today. “In the U.S. alone, 500 million doses of these vaccines were administered in the past year, and much more worldwide.”
In the oncology space, nanomedicine is most frequently used to improve precision of chemotherapy delivery, thus potentially reducing off-target adverse events. Researchers also seek to harness nanotechnology to improve immunotherapy safety and efficacy.
“The research activity in nanomedicine has been tremendous — if you look at the number of publications that had the word ‘nanoparticle’ in them 20 years ago, it was very, very few,” Grodzinski said. “Some might argue that the translation and clinical implementation of these technologies isn’t happening fast enough, but that is, to some extent, true of any new technology. If you look at the last 5 years, there were three approvals of different nanotechnologies for cancer. I think to keep moving this field forward, it’s important to engage oncologists and practicing physicians in the technology at the early stages even more.”
Healio | HemOnc Today spoke with clinicians and researchers about current applications of nanomedicine in oncology, potential uses in immunotherapy and targeted drug delivery, and what the future may hold for the field.
Current uses in oncology
The most common application of nanomedicine in cancer is for targeted delivery of chemotherapy drugs, according to Betty Y.S. Kim, MD, PhD, of the department of neurosurgery at The University of Texas MD Anderson Cancer Center.
“The most common cancer nanomedicine that has been approved by the FDA and used in the clinic are nano-formulated chemotherapies,” Kim told Healio | HemOnc Today. “These include protein-based nanoparticles or lipid nanoparticles that deliver chemotherapeutic agents to tumors with improved pharmacologic profiles and reduced toxicities.”
The drug that is perhaps best known in this category is doxorubicin hydrochloride liposomal injection (Doxil, Baxter), which consists of doxorubicin encapsulated in a closed lipid sphere. Another chemotherapy drug available in a protein-based nanoparticle formulation is paclitaxel protein-bound particles for injectable suspension (Abraxane, Bristol Myers Squibb).
“These are the most well-known, but there are a number of different formulations in the U.S., as well as in some other countries,” Grodzinski said. “In general, with Abraxane and Doxil, the major advantage is the reduction of side effects of the treatment.”
For example, Grodzinski said use of freestanding doxorubicin can lead to cardiomyopathy.
“If you formulate it into liposomes like Doxil does, the possibility of cardiomyopathy is significantly reduced, so it’s a big deal from that perspective,” he said. “Abraxane also reduces the infusion reaction that Taxol [paclitaxel] can cause due to the use of organic solvent, cremophor, in its formulation. If you look at the use of paclitaxel as a freestanding drug vs. Abraxane, we see sales of Abraxane are growing rapidly, and the use of paclitaxel as a freestanding drug is tapering off, even with Abraxane being much more expensive than paclitaxel alone. Oncologists are starting to appreciate the value of it, because it improves the comfort of the patient.”
Additionally, research is now focusing on combination therapies in which one nanoparticle can deliver more than one therapeutic agent. These include Vyxeos (Jazz Pharmaceuticals), a liposome-encapsulated combination of the chemotherapy drugs cytarabine and daunorubicin, which has received FDA approval for treatment of adults and children aged at least 1 year with therapy-related acute myeloid leukemia.
“The advantage is that you can determine the exact ratio of these two drugs, packaging them into one particle,” Grodzinski said. “It was shown that, depending on the ratio of the two, this treatment can be more or less effective.”
Grodzinski said a possible next step for nanomedicine will involve combining nanoparticle-based treatments of different modalities together or coupling them with more traditional cancer treatments, to determine whether such combinations might improve efficacy.
“There are also some attempts to enhance the effectiveness of radiation using nanoparticles,” he said.
Grodzinski discussed the radiation enhancer NBTXR3 (Hensify, Nanobiotix), which received European market approval in 2019 for treatment of locally advanced soft tissue sarcoma. NBTXR3 is designed to destroy tumors and trigger the immune system for local tumor control and treatment, and is used to strengthen the effect of radiation therapy.
“Hensify relies truly on the property of the material. It is a hafnium oxide, which is the oxide of a heavy metal,” Grodzinski said. “It is delivered to the tumor and basically localizes absorption of the external radiation and creates secondary electrons that generate the localized treatment. The nanoparticle, in this case, is used as a vehicle to deliver the drug, the material properties of the nanoparticle itself provide an efficacious advantage.”
‘Super shuttle’ for immunotherapy
Research in cancer nanomedicine has extended to immunotherapy, for which it is believed to hold promise, according to Kim.
“One of the major advantages of nanomaterials is that they readily interact with the body’s immune system. Therefore, it provides a strategy that can deliver therapeutic agents to immune cells more effectively — a ‘super shuttle,’ per se,” she said.
Grodzinski said efforts to develop immunotherapy applications of nanoparticles are in early stages, but that the area is of great interest among those who work with this technology.
“Preclinical demonstrations show nanoparticles have the advantage of being able to deliver several different antigens or their combination with adjuvants at the same time, which can boost the effectiveness of the treatment in one nanoparticle system,” he said. “A few startup companies are beginning to translate the nanoparticle application into immunotherapy. Those are mostly phase 1 or phase 2 clinical trials.”
In a research collaboration with Mayo Clinic, nanomedical company NaNotics LLC plans to develop and evaluate a novel absorptive nanoparticle for use in cancer treatment.
The company’s nanoparticles, NaNots, treat disease by capturing and clearing pathogenic molecules from the blood. The goal of the current collaboration is to generate a NaNot that targets the soluble form of the PD-L1 protein, submit an investigational new drug application to the FDA and initiate human trials within 18 months.
“NaNots invert the normal drug paradigm — whereas drugs add molecules to the body, NaNots induce a net depletion of molecules from the body,” Lou Hawthorne, CEO of NaNotics and inventor of NaNots, said in an interview with Healio | HemOnc Today in March. “It’s an injectable nanoparticle that captures a target and clears it from circulation via macrophage phagocytosis. NaNots are only active against soluble targets in blood. A drug will hit the soluble form of a target of interest, but it’s also going to hit membrane forms that perform vital regulatory functions, leading to toxicity.”
Cancer cells with high levels of PD-L1 inhibit the immune system from attacking tumors, allowing them to progress.
“Recently we’ve learned that much of the inhibitory action of PD-L1 is actually carried out by soluble PD-L1, secreted by tumors,” Hawthorne said. “We’ve also learned that many normal cells employ membrane PD-L1 as part of their ‘don’t eat me’ signaling system, which is why drugs against either PD-L1 or its cognate PD-1 receptor are so toxic. The unique specificity of NaNots for soluble targets enables them to deplete soluble PD-L1 without disturbing membrane PD-L1 at all. Depleting soluble PD-L1, which isn’t normally present in significant concentrations, should be completely nontoxic except to the tumor, which relies on soluble PD-L1 for its defense.”
Another potential nanomedicine approach to cancer immunotherapy involves exosomes, according to Kim.
“[These] are cell-secreted nanoparticles that have been designed to carry immune-modulating agents to activate antitumor responses, a platform that is still in development but might one day provide new approaches,” she said.
Kim also discussed previous research into quantum dots, nanocrystals that give off an array of very bright colors depending on the crystal size.
“Despite their great promise in use as a potential contrast agent, quantum dots have not been used in the clinical setting due to concerns of toxicity,” she said. “The most common variety of quantum dots are made from cadmium and selenium semiconductors. However, these are toxic heavy metals; thus, there are efforts into engineering quantum dots with less harmful elements, such as carbon or silica.”
‘Target-or-clear’ paradigm
One nanomedicine innovation that has shown diagnostic and therapeutic potential is Cornell dots.
Introduced in 2005, the dye-encapsulating fluorescent silica nanoparticles initially had been developed in the Cornell University lab of Ulrich B. Wiesner, PhD, as an ultrabright imaging tool to visualize tumors for better informed decision-making in the surgery room.
A single ultrasmall Cornell dot contains multiple dye molecules enclosed in a silica shell that can be as small as 3 to 4 nanometers in diameter. The dots are coated with oligomeric polyethylene glycol, which protects them from being recognized by the body as foreign substances.
Since the technology’s introduction, Elucida Oncology Inc., a biotechnology company Wiesner co-founded, has further developed the nanoparticles, now known as C’Dots, and will assess them for therapeutic use in targeted drug delivery among patients with advanced, recurrent or refractory cancers.
Wiesner said he and the team molecularly engineered the C’Dots delivery system with the intention of overcoming well-known issues of existing therapies, including those of the current gold standard in cancer therapeutics, antibody-drug conjugates (ADCs).
“Through the work with our collaborators at Memorial Sloan Kettering Cancer Center [MSKCC], we created the ‘target-or-clear’ paradigm — particles either target the tumor or are eliminated via the kidneys and do not accumulate elsewhere in the body — originally for diagnostic applications,” Wiesner said in an interview with Healio | HemOnc Today earlier this year. “But we quickly saw that we also get good accumulation within solid tumors. Because the particles are so small, they diffuse much more rapidly than larger particles. This faster diffusion enables them to penetrate solid tumors much more effectively than larger entities. This is true even with the most successful current developments in cancer therapy, which are basically ADCs that are about three times as big as C’Dots.”
“They get stuck on the tumor surface,” Wiesner said. “In early clinical trials, folks at MSKCC resected tumor tissue and saw that C’Dots, which are fluorescent and easy to use, distributed beautifully through these solid tumors. Together with their unusually high drug-loading capacity, that got us very excited about therapeutic applications.”
Involving clinicians
Grodzinski said innovation and research into nanoparticles for cancer diagnosis and treatment have shown no signs of slowing down.
“I think in general, any new biological discovery can be coupled with nanoparticle use when the effective in vivo delivery is required,” he said. “There are also diagnostic applications of nanoparticles and nanodevices where researchers are trying to use tests based on nanotechnology to differentiate or determine which subgroups of patients will be more amenable to cancer treatment.”
Despite the many possibilities that have unfolded, nanomedicine research is not without challenges.
Some have questioned the ability of in vitro testing to predict the efficacy of nanoparticle therapies in the human body. In a study published in Biophysics Reviews, researchers characterized the “low reliability and validity of cell culture testing for therapeutic applications.”
“I think this discrepancy isn’t unique to the nanomedicine field, as this is a challenge that we face for any biological research,” Kim said. “The environment/conditions presented in culture is vastly different from those seen in vivo. How we can accurately recapitulate the in vivo environment in a culture dish is the ultimate question.”
Grodzinski said another way to improve advancement of nanomedicine is to involve clinicians earlier in the process of developing treatments and/or diagnostics.
“Selecting the appropriate tumor for the treatment and having a physician participating in an appropriate early design of the nanoparticle therapeutic construct is critically important for the success of the trial,” he said. “It is a challenge — clinicians are very busy, but many of them at research institutions are recognizing the value of nanomedicine. It is a hope that future breakthroughs in nanomedicine, coupled with broader engagement of clinicians, will move the field and its implementation into clinical practice forward.”
- References:
- Berger S, et al. Biophysics Rev. 2022;doi:10.1063/5.0073494.
- Fleischman T. Prime time: First therapeutic clinical trial of C’Dots underway. Cornell Chronicle. Available at: https://news.cornell.edu/stories/2021/12/prime-time-first-therapeutic-clinical-trial-cdots-underway. Dec. 8, 2021.
- Jazz Pharmaceuticals announces FDA approval of additional indication for Vyxeos (daunorubicin and cytarabine) for the treatment of secondary acute myeloid leukemia in pediatric patients (press release). http://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-fda-approval-additional. Published March 30, 2021. Accessed May 9, 2022.
- Nanobiotix announces first-ever radioenhancer to receive European market approval (press release). www.nanobiotix.com/wp-content/uploads/2019/06/PR_Nanobiotix_marquage_CE_04042019_VF-1.pdf. Published April 4, 2019. Accessed May 9, 2022.
- NaNotics to collaborate with Mayo Clinic on nanomedicine cancer treatment (press release). www.nanotics.com/pdfs/Mayo_Clinic_and_NaNotics_to_Collaborate%20on_Novel_Nanomedicine_for_Treating_Cancer.pdf. Published Jan. 4, 2022. Accessed May 9, 2022.
- Tinkle S, et al. Ann N Y Acad Sci. 2014;doi:10.1111/nyas.12403.
- For more information:
- Piotr Grodzinski, PhD, can be reached at National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD 20892-9725; email: grodzinp@mail.nih.gov.
- Lou Hawthorne can be reached at NaNotics LLC, 531 Midvale Way, Mill Valley, CA 94941; email: lou@nanotics.com.
- Betty Y.S. Kim, MD, PhD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: bykim@mdanderson.org.
- Ulrich B. Wiesner, PhD, can be reached at 330 Bard Hall, Materials Science and Engineering, Cornell University, Ithaca, NY 14853; email: ubw1@cornell.edu.
Click here to read the sidebar to this Cover Story.
Collapse
Read more about
Click Here to Manage Email Alerts