Nature-Inspired Nanoparticle Adiposomes Enable Targeted Delivery of Hydrophobic Drug for Anti-Cancer Treatment

Summary

Inspired by biological mechanisms, the development of adiposomes offers a solution to the challenges faced by hydrophobic drug delivery. Here, the widely used chemotherapeutic agent docetaxel is used to demonstrate the improved safety and efficacy of adiposome delivery compared to conventional platforms in animal models. The results support the potential of this innovation to improve new and existing therapeutic compounds in a variety of disease contexts.

Background

An increasing number of drug targets are being identified inside the cell, opening new avenues for therapeutic development.(1) To reach intracellular targets, compounds must cross the outer lipid bilayer, and to facilitate this many are designed with hydrophobic properties.(2) However, this raises an issue in delivering such compounds to target cells through the hydrophilic environment of the blood. One strategy is to encapsulate drugs in hydrophilic shells with lipid cores called nanoparticles, but poor drug-delivery and immune responses remain barriers to therapeutic implementation.(3–5)

Interestingly, evolution has already solved the problem of transporting hydrophobic molecules through a hydrophilic environment, as this is required by innate biological processes in the human body. It is the endogenous machinery dedicated to this purpose, involving lipoproteins and lipid droplets, which inspired the authors of this preprint in the design of their own nanoparticles called adiposomes.

Whereas other nanoparticles such as liposomes consist of a phospholipid bilayer membrane surrounding an aqueous core, adiposomes have a phospholipid monolayer membrane and a lipid core (Fig. 1A). This design offers advantages over other nanoparticle formulations that are associated with drug leakage and instability, limited loading capacity and inefficient drug delivery.(5)  Thus, adiposomes represent a novel platform for the delivery of hydrophobic drugs to intracellular targets, offering increased biocompatibility and pharmacologic properties.

Key findings

Docetaxel-loaded adiposomes’ cytotoxicity was comparable to docetaxel injection in vitro

Docetaxel is an example of a hydrophobic intracellular targeting drug, which is used as first line treatment in a variety of cancers. The authors selected this drug to test the functionality of adiposomes. Initially, the authors evaluate whether docetaxel loaded adiposomes (DTX-Ad) are as effective and work in the same way as clinically used docetaxel injection (DTX-Inj). Quantification of cell death using cytotoxicity assays yielded similar results in cancer cell lines exposed to either treatment, demonstrating comparable efficacy. Using immunofluorescent staining and cell cycle arrest assays, the authors further demonstrated that DTX-Ad induce cytotoxicity through the same mechanism as DTX-Inj: through destabilisation of the cytoskeleton and cell cycle arrest between G2 and M phases.

Antitumour efficacy and safety of docetaxel-loaded adiposomes were demonstrated in multiple in vivo cancer models

The authors then moved on to exploring the effectiveness of DTX-Ad in vivo and showed significant tumour growth suppression in three separate cancer mouse models. The antitumour effects of DTX-Ad were generally comparable to DTX-Inj but the former resulted in less weight loss and minimal-to-no reduction in immune cell counts, unlike the latter. In one model, DTX-Ad performed better than another commercial chemotherapeutic agent, paclitaxel, in terms of tumour inhibition.

Overall, the results support that DTX-Ad effectively inhibits tumour growth in vivo, with less toxicity than DTX-Inj.

Organ specific targeting of docetaxel-loaded adiposomes increased specificity and antitumour effects

Despite these successes, the authors wanted to enhance the antitumour effects of DTX-Ad even further and aimed to do so through organ targeting modifications. Lung-enriched protein binding peptides and ApoE were attached to the outside of DTX-Ad for targeting of the lung and liver, respectively (Fig. 1B). Modified DTX-Ad were shown to selectively accumulate in the target organ in vivo, with lung targeting DTX-Ad delivering 8.7-fold higher, and liver targeting DTX-Ad 16.8-fold higher, concentrations of docetaxel compared to DTX-Inj. Tumour inhibition in cancer mouse models was significantly greater with modified DTX-Ad treatment versus injection, and liver targeting DTX-Ad even achieved total eradication. The enhanced performance did not come at the expense of safety, as modified DTX-Ad did not induce blood cell rupturing, nor a decrease immune cell counts, or otherwise cause noticeable systemic toxicity, unlike DTX-Inj.

Ultimately, these findings support the preprint authors’ achievement in developing a nanoparticle delivery system with improved efficacy and tolerability compared to the most used marketed formulation.

Importance

Therapeutic action is metered by the success of therapeutic delivery, which is especially challenging for hydrophobic small molecule drugs. Docetaxel is just one example where this problem is currently being addressed at the cost of systemic tolerability. Adverse effects have a significant impact on a patient’s quality of life and may result in discontinuation, even when a drug is effective. Adiposomes, through enhanced target specificity and better safety, represent a novel solution to overcoming these limitations on therapeutic potential. This is especially important considering the shifting of the therapeutic landscape toward small molecule drugs, prompted by the increased identification of intracellular drug targets.

Questions for the authors

• How does the loading capacity of adiposomes compare to other nanoparticles; have you investigated the dynamics of loading with multiple drugs?
• Is there much difference between the volume of adiposome formulation and solvent based injection needed for the same dose of docetaxel, as this may confer different storage space requirements?
• How does the production of adiposomes compare with other nanoparticles and delivery platforms in terms of cost and scalability?
• Do you have any plans for evaluating adiposomes in other animal models or patients?

References

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doi: https://doi.org/10.1242/prelights.44199

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