Employing Synergistic Strategies to Advance Nanomedicine

By Megan Craig, M.Sc.Feb 9 2022

Therapeutic and drug delivery systems built with nanomaterials contain molecules ranging in size. Due to developments in lipid nanoparticle (LNP) technology, the first SARS-CoV-2 (COVID-19) vaccines built with siRNA therapy and mRNA delivery systems were formed.  ​​​​​​​

​​​​​​​Image Credit: Love Employee/Shutterstock.com

Although LNPs, as well as other nanoparticles, have demonstrated use in stabilizing and delivering cargo to target areas, targeted nanomedicine remains difficult to achieve in practice. 

There is now a significant divergence between fundamental science and translational progress in the field of nanomedicine.

To advance this field, researchers will need to overcome the barrier that prevents clinical applications of nanomaterial systems. 

By designing strategies and methodologies that aim to investigate the therapeutic interactions between these nano-based technologies and biological systems, significant progress can be made in the field of nanomedicine. This idea is illustrated in Figure 1. 

Figure 1. Development of nanomaterials systems for drug delivery is traditionally focused on the study and optimization of materials properties. To overcome biological delivery barriers, we must shift the focus to understanding the interactions of cells and tissues with nanocarriers. We can achieve this through integrated approaches, including the use of nanoparticle libraries, pooled screening, and omics characterization. Image Credit: Boehnke and Hammond, 2022 

The introduction and increased accessibility of high-throughput sequencing methods has accelerated the field of therapeutic genomics. As shown in Figure 2, these essential concepts are starting to be used in nanomedicine, presenting an unprecedented potential to develop the discipline.

Figure 2. Illustrated examples of nanocarrier screening approaches. Traditionally, candidate formulations are tested iteratively, in one or two models at a time, with a focus on materials property testing. Through the use of pooled cell screening, the same formulations can be screened against hundreds of cell lines simultaneously, providing insight into the biological features mediating successful nanocarrier targeting and uptake. Alternatively, barcoding strategies can be implemented to pool nanocarriers for accelerated biological screening. Image Credit: Boehnke and Hammond, 2022

Advancements in Nanocarriers

Extensive, combinatorial libraries of lipid and polymer-based nanocarriers for gene and drug delivery applications have resulted from advancements in nanocarrier synthesis, including lipid nanoparticles for RNA transport, chemically varied core–shell NPs, and lipocationic polyesters.

Research has shown that successful transfection is dependent on three key factors, each of which is controlled by different physicochemical features of the nanocarrier: RNP uptake (protonation state),  hydrophobicity, and cellular toxicity (polyplex diameter).

One method for swiftly screening a large number of drug delivery vehicles in a single system is to use barcoded nanocarriers. Early reports of barcoded nanoparticles depended on imaging-based decoding algorithms with restricted clinical implications, and nanocarrier barcoding strategies have come a long way.

In addition, DNA barcodes have been integrated into liposomes in combination with small molecule therapies to analyze both delivery success and therapeutic efficacy collectively manner. The efficacy of small molecule delivery can be assessed using this method by combining treatment response (e.g., viability) with the number of DNA barcodes per cell.

While this research offers a simple way to link liposome delivery to treatment success, it also exposes the limitations of nucleic-acid-based barcodes.

Pooled screening has begun to illustrate the power of DNA barcodes in accelerating nanocarrier development.

Alternative barcoding systems, particularly those that enable direct nanocarrier tracking in vivo and are compatible with various drug delivery vehicles, are urged to be considered by the field.

To deposit layers of operational polyelectrolytes on a charged surface, layer-by-layer (LbL) assembly can be used. Besides therapeutic delivery, the modular structure of LbL assembly allows for basic research into the impacts of specific nanocarrier parameters, as demonstrated in Figure 3.

Figure 3. Layer-by-layer assembly can be used to electrostatically coat a wide range of nanoparticle cores with functional polyelectrolytes. The approach enables complete coating of the carrier core and thus decouples the outer layer functionality from physical or chemical characteristics of the core. Image Credit: Boehnke and Hammond, 2022

Figure 4 shows how LbL assembly is used to develop NP libraries to assess new designs with tumor-targeting properties.

Novel surface chemistries with distinct intracellular transport properties and remarkable affinity for ovarian cancer cells over non-neoplastic cells have been identified using this strong NP screening technique.

Figure 4. Layer-by-layer assembly enables the generation of nanocarrier libraries wherein one component is varied while all others are kept constant. Illustrated here is an example of a common nanoparticle core and polyelectrolyte layer being separately coated with a range of polyanions to generate a nanocarrier library focused on evaluating surface chemistry effects. Image Credit: Boehnke and Hammond, 2022

Results and Discussion

Researchers believe that overcoming existing challenges will require two synergistic strategies: (1) thorough in vitro screens to help understand key cellular qualities resulting in nanocarrier therapeutic success, and (2) the advancement and use of adequate, relevant models to relate cellular and tissue-specific nanocarrier selectivity with effective circulation and trafficking properties.

Because of biological heterogeneity, there are various challenges limiting the successful translation of new therapeutic agents in the field of small molecule drug discovery.

Restricted preclinical screens that fail to grasp the diversity and complexity of human patients are often blamed for the absence of reproducible data and failing to reproduce efficacy beyond basic models.

A lack of appropriate preclinical models to completely assess the therapeutic efficacy of nanomedicine has been proven. Models should be able to accurately depict human complexity and disease, as well as anticipate response to tested treatments.

By shielding encapsulated cargo from degradation, extending circulation duration, and reducing harmful side effects, the development of nanocarriers for therapeutic delivery applications has already resulted in substantial clinical improvements.

Translational successes in targeted medication delivery, on the other hand, have been very limited.

The continuous development and utilization of relevant preclinical models, such as multicellular organoids and mice models capable of replicating human immunological responses, will be required to further enhance the current understanding of the nano-bio interface.

Finally, future research will be able to holistically discover the critical characteristics influencing efficient cell targeting and uptake, from both materials and biology perspectives, by comprehensively combining these methodologies, as illustrated in Figure 5.

Figure 5. Informed nanocarrier design is possible through the use of nanoparticle barcodes, pools, and libraries, which can be interfaced with high throughput screening, biological profiling, and physiological in vitro and in vivo models. Through these integrated approaches, we can gain a more thorough understanding of the biological characteristics necessary for successful delivery of therapeutics. Image Credit: Boehnke and Hammond, 2022

Conclusion

Since there is presently a significant gap between in vitro and in vivo nanocarrier performance due to a lack of mechanistic knowledge into the causes of these failures, physiologically representative models must be developed and implemented to allow translation of suitable candidates recognized through in vitro screens.

Developing and testing customized mouse models is often beyond the scope of nanotechnology-focused research teams. As a result, researchers should form partnerships with biological and clinical researchers to benefit from their knowledge in disease-focused preclinical testing.

By providing scientists and physicians with the tools given by nanomedicine to tackle unaddressed difficulties, these interdisciplinary methods also pave the way for a successful nanomedical future. 

Continue reading: Manifesting Multidisciplinary Nanomedicine Research with the MMS

Journal Reference:

Boehnke, N., & Hammond, P. T. (2022) Power in Numbers: Harnessing Combinatorial and Integrated Screens to Advance Nanomedicine. JACS Au, 2(1), pp. 12–21. Available Online: https://pubs.acs.org/doi/10.1021/jacsau.1c00313.

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