An update on synthetic high-density lipoprotein-like nanoparticles for cancer therapy

ABSTRACT

Introduction: Significant clinical correlations have been observed between serum high-density lipoprotein (HDL) cholesterol and cancer risk, outcomes, and patient response to specific treatments. While the biological processes underlying these correlations remain unclear, evidence suggests that HDLs actively inhibit tumor progression through a variety of mechanisms. As a result, synthetic HDLs have emerged as attractive agents for targeted cancer therapy.

Areas covered: We present a focused review of recent developments in the use of synthetic HDLs for cancer therapy, including roles in drug delivery, RNAi, monotherapy, and immunotherapy. In addition to historic references relevant to the field, we searched the following databases for recent articles published from January 1^st, 2015 – May 1^st, 2019: MEDLINE, Web of Science Core Collection, and Google Scholar.

Expert opinion: Synthetic HDLs have already been used in human patients for cardiovascular disease, and have proven to be effective anticancer agents in pre-clinical testing, which should pave the way for future clinical trials in the setting of cancer. Given the growing notoriety of dysregulated cholesterol homeostasis as a key mechanism of cancer progression, and the immense success of synthetic HDLs in animal models, synthetic HDLs are well-poised to make significant strides toward the clinic as cancer therapy.

KEYWORDS:

• Cancer therapy
• cholesterol
• drug delivery
• high-density lipoprotein
• immunotherapy
• nanoparticle
• siRNA
• myeloid-derived suppressor cell

Article highlights

• A diverse set of synthetic HDL platforms are currently being evaluated as standalone cancer therapies or as vehicles for the targeted delivery of therapeutics. Synthetic HDL platforms are generally regarded as safe, which should facilitate their translation to the clinic.

• Synthetic HDLs have demonstrably reduced tumor burden in mouse models for an expansive range of tumor types, including lymphoma, melanoma, breast cancer, prostate cancer, ovarian cancer, pancreatic cancer, and colon cancer.

• Synthetic HDLs have recently been investigated as immunotherapeutic agents for cancer. Three different HDL mimics were shown to induce beneficial immunogenic transformations to the tumor microenvironment, while concomitantly reducing tumor burden in mouse models of melanoma, colon cancer, and pancreatic cancer. Specifically, synthetic HDLs were found to inhibit the immunosuppressive activity of MDSCs and Tregs, while activating anti-tumor immune cells including effector T cells and patrolling monocytes.

• Synthetic HDLs continue to be effective as drug delivery agents, and as RNAi delivery agents, by exploiting the intrinsic carrier properties of native HDLs.

• There is considerable debate over which HDL sub-species are responsible for the beneficial functions of HDL in the settings of cardiovascular disease and cancer. Recent evidence indicates that mature, spherical HDL species may be responsible for many beneficial effects of HDLs.

Acknowledgments

The authors are grateful to Michael Plebanek for assistance with graphic production.

Declaration of interest

CS Thaxton founded a biotechnology company, Zylem Biosciences, focused on translating high-density lipoprotein nanoparticles into the clinic. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

CS Thaxton received funding from the Simpson Querrey Institute’s Center for Regenerative Nanomedicine at Northwestern University. SE Henrich received funding from the NIH with an NRSA individual graduate fellowship under Grant number 5 F30 CA225133-02.