Nanomedicine Boosts Cancer Therapy Efficacy

Unlike two decades ago, when nanomedicine was “the new kid on the block,” today, it is fully integrated into basic, translational, and regulatory sciences and has become an integral part of our lives.

Healthy people experience it firsthand when they use over-the-counter lateral flow gold-nanoparticle-containing diagnostic kits or regulatory health agency-approved lipid-nanoparticle-based mRNA formulations intended for protection against SARS-CoV-2 infection.

Patients experience nanomedicines when they undergo therapy with one of the following formulations: Abraxane (nano-albumin bound paclitaxel), Doxil (liposomal doxorubicin), Vyxeos (liposomal daunorubicin and cytarabine), Onivyde (liposomal irinotecan), Depocyt (liposomal cytarabine), Fyarro (nanoalbumin bound sirolimus), AmBisome (liposomal amphotericin), Onpattro (lipid-nanoparticle-formulated transthyretin-directed small interfering RNA), or Feraheme (iron oxide nanoparticles). More cancer nanomedicines approved for clinical use in the US and/or other countries are summarized by the US National Cancer Institute (NCI) at https://www.cancer.gov/nano/cancer-nanotechnology/current-treatments.

Common features of nanomedicines include particle sizes less than 350 nm, neutral charge, spherical shape, systemic (intravenous) administration, and indications for cancer treatment1. However, there is a growing movement to utilize nanoparticles for other indications, particularly for genetic disorders and infectious diseases, as well as for local administration routes, such as intramuscular and intratumoral.

Liposomes are the most used carriers in nanomedicines approved for clinical use. According to a recent report by the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER), the use of nanotechnology in drug products reviewed by the FDA dates back to 1973; during the time between 1973 and 2015, the most common types of nanomedicines were those utilizing liposomes, nanocrystals, emulsions, iron-polymer complexes, and micelles2. This trend in the types of nanomaterials matches those seen by the NCI Nanotechnology Characterization Laboratory (NCL)3.

Translating nanomedicines from the bench to the clinic, however, is not a trivial task, even for an experienced drug developer. Complexity in design, characterization, manufacturing, and regulatory approval, along with the perception bias of investors and the general public, as well as high translational costs, create significant roadblocks on the path to the clinic for nanomedicine. For example, CYT-6091, a PEGylated gold nanoparticle formulated to deliver recombinant cytokine tumor necrosis factor-alpha (TNFa) directly to tumors, successfully completed two clinical trials in the US over 15 years ago4 (NCT00356980 and NCT00436410 in https://clinicaltrials.gov/search?term=CYT-6091). These studies demonstrated that, unlike the native protein, CYT-6091 enables the safe systemic administration of TNFα at doses that otherwise were toxic. Unfortunately, the 2007–2009 US economic recession hindered further clinical development of this promising cancer nanomedicine. CYT-6091 is one of many promising nanomedicines that have shown clear clinical promise but have yet to cross the so-called “valley of death” in drug development to reach commercial sales.

Nanomedicine is defined as “the application of nanotechnology to medicine” and it is making an increasingly prominent mark on present-day medicine. In 2020, nanomedicine was beyond instrumental to help halt the COVID-19 pandemic: it not only provided the tools to assist in disease detection, via colloidally dispersed gold nanoparticles surface-functionalized with recognition motifs in lateral flow devices to bind corona virus spike proteins in sputum samples, but it has also crucially enabled the use of mRNA as a drug, and the development of highly effective vaccines against COVID-19.

Based on similar principles, nanovaccines are changing the way cancer patients can be treated. By loading nanoparticles with mRNAs encoding for antigens uniquely expressed by cancer cells in individual patients, the immune system can be trained to specifically recognize these cells, thereby boosting the number of long-term cures when combining these treatments with antibodies that inhibit immune checkpoints.

A bit more historically, liposomal and protein-based nanomedicines, like Doxil and Abraxane, have been creating patient benefit for 20–30 years now, particularly by making chemotherapy treatments better tolerable. Follow-up formulations, like Vyxeos, in which two different drugs are combined in one liposome in a synergistic ratio, hold promise to also significantly improve therapeutic efficacy. Similar “multi-drug nanomedicines” are anticipated to increasingly impact the clinical oncology landscape in the future.

Regarding failures, like for many other anticancer drugs, not all nanomedicines have lived up to their promise. Prominent examples of this include actively targeted formulations, in which recognition motifs are used to help deliver drugs more efficiently to and into cancer cells. The translational success of these formulations could have profited from the use of biomarkers, e.g., via staining tumor tissues for the receptors that are being addressed, similar to the clinical development of antibodies and antibody-drug conjugates.

Preclinical evidence of nanomedicine safety and efficacy at doses, dose regimens, and routes of administration that match their clinically intended use is crucial. However, the successful preclinical phase per se is insufficient to guarantee progress to the next stage—the clinical phase. Other equally essential components are (1) securing intellectual property rights in the technology and each of its components, such as antibodies, aptamers, and active pharmaceutical ingredients, (2) establishing a reliable supply chain of all formulation components, (3) ensuring that the technology is compatible with scale-up, (4) developing and optimizing manufacturing procedures suitable for the large-scale production of pyrogen-free nanomedicine, (5) identifying current good manufacturing practice (cGMP) facility adequately equipped for the given nanomedicine production, (6) understanding critical quality attributes of the nanomedicine, (7) establishing and validating a set of analytical assays for in-process characterization and batch release of the nanomedicine, (8) understanding the regulatory path and associated requirements, and (9) securing sufficient funding.

The compatibility of nanomedicine with scale-up is a common bottleneck in the translational journey. Preclinical studies often rely on benchtop synthesis, producing milligrams of nanomedicine. Such benchtop milligram-scale procedures are often incompatible with large-scale GMP production and require significant changes to scale up by several orders of magnitude to yield sufficient quantities, on the order of kilograms, for animal safety and tolerability tests that support subsequent clinical studies. Often, a change in the process is required, and a new process often yields a new product with different physicochemical and, consequently, biological properties. For example, film rehydration is a reliable method commonly used to produce milliliter volumes of liposomes for preclinical studies; however, it is not suitable for large-scale production. Substituting this method with alternative methods—ethanol injection or reverse-phase evaporation—leads to changes in particle size and homogeneity and requires the introduction of additional steps to remove organic solvents5. Lipid nanoparticles (LNPs) produced by a coaxial turbulent jet mixer are small, have a narrow size distribution, and exhibit high oligonucleotide encapsulation efficiency6. In contrast, LNPs produced by a microfluidic mixer are larger and have lower encapsulation efficiency of oligonucleotides6. According to the experience of the Nanotechnology Characterization Laboratory (NCL), scale-up challenges, if not addressed in a timely manner, result in an unrecoverable loss of time and funding, thereby hindering the clinical translation of promising nanomedicines.

The majority of cancer nanomedicine development is restricted to preclinical studies with few making it to the clinic. What preclinical evidence is most important to indicate that a therapy may have the potential to progress to the next stage?

There is indeed a disconnect between the number of preclinical papers and the number of nanomedicines making it to patients. Part of this results from how the academic—particularly nanomedicine—climate has developed over the years, with an over-focus on fancy materials and high-impact publications, rather than on understanding (and doing) what it takes to make progress towards translation.

It is OK for academic research(ers) to push the boundaries of what we can make. But then the results reported in papers should better contextualize the engineering advances and avoid overly optimistic claims on how, e.g., pancreatic cancer or glioblastoma treatment will now change using the new nanomaterial generated. To promote progress, technology-push and clinical-pull should meet in the middle. This requires in-depth understanding of not only disease biology and pathophysiology (in order to design active pharmaceutical ingredients (API) and nanomedicines accordingly), but also of key clinical challenges and practical limitations (to properly translate drugs and drug delivery systems).

Some of the disconnect between preclinical and clinical progress will likely resolve in the future, now that we have realized that biomarkers are crucial to identify the right patients to include in cancer nanomedicine clinical trials. Unlike for almost all other second-generation anticancer drugs, like antibodies, antibody-drug conjugates and tyrosine kinase inhibitors, no biomarkers have yet been established for nanomedicine patient stratification.

What would also help to promote successful translation is if we would agree on the use of “standardized” tumor models to directly head-to-head compare novel (nano)drugs versus the current standard-of-care drug treatment. Such models could e.g., include one syngeneic allograft and one patient-derived xenograft, with both properly mimicking key features of the cancer in question. If the new (nano)drug outperforms the best available drug in both models, there is clear promise for further development.

Nanomedicine developers have numerous factors to consider. Among some initial considerations are the intended indication (e.g., cancer or infectious disease), organ or tissue affected by the disease (e.g., brain or peripheral blood), clinically intended route of administration (e.g., systemic vs. local), the known liability of a drug and nanotechnology carrier (e.g., cardiotoxicity, hypersensitivity reaction), and desired outcome (e.g., reduced toxicity, prolonged release, tissue-specific targeting). Considering these nuances helps to select the nanotechnology platform, identify the active ingredients and excipients, determine whether additional designs, such as tissue-specific targeting, are necessary, and understand what safety studies would be needed. Once nanomedicine is designed, its efficacy must be confirmed in a biological system. There are numerous available models, both in vitro and in vivo, for studying efficacy, and their selection depends on the intended use of nanomedicine.

If it is known that nanomedicine will come in contact with blood, analysis of its hemocompatibility is essential. Such tests include understanding nanoparticle interactions with erythrocytes, the coagulation system, which involves platelets and plasma coagulation factors, as well as the complement system. Additionally, it is crucial to comprehend the interactions between nanoparticles, immune cells, and plasma proteins, as these interactions significantly influence the clearance of nanomedicine and potential immunotoxicity. Standardized hemocompatibility and immune-compatibility protocols are available on the NCL website: https://www.cancer.gov/nano/research/ncl/protocols-capabilities#immunology-protocols. Many of these assays exhibit good in vitro-in vivo correlation, thereby helping to reduce the use of animals in research.

Other safety considerations include conducting general toxicity studies and analyzing nanoparticle toxicity to liver and kidney cells, as these cells represent organs that serve as common routes of nanoparticle clearance from the body. More standardized protocols and guides for in vivo characterization are also available to the nanotechnology research community on the NCL website https://www.cancer.gov/nano/research/ncl/protocols-capabilities#pharmacology-and-toxicology-protocols.