Tremendous advancements in cancer treatment research have been made in the last 50+ years. No longer is a diagnosis accompanied by utter hopelessness; thanks to countless hours of research, patients are now presented with an array of treatment options that may prolong their lives or even eradicate their cancer completely. However, many obstacles to an absolute cure remain: most concerning of these obstacles is metastasis, especially to the central nervous system (CNS). Considering the delicacy of these organs, any metastases to the CNS leave limited viable options for an afflicted patient.
The blood-brain barrier (BBB) acts as a protective mechanism that prohibits invasion of potentially harmful agents to the brain; while necessary, this barrier also prevents most small molecular drugs and anti-cancer macromolecules developed thus far from effectively delivering treatment to metastases in the CNS. With this obstacle looming, treatment options lose their promise—but for our group, with this obstacle came fascination, followed by a promising solution.
The advent of nanotechnology has garnered intrigue from scientists in nearly all areas of immunotherapy. With an eye to the potential for engineering a nanosized capsule structure (~30nm) in which we could freely encapsulate macromolecules and manipulate a variety of properties on the surface, our group focused on developing a nanocapsule capable of crossing the BBB that could administer treatment to previously untreatable metastases in the CNS. Utilizing a polymer shell capable of transport via choline transporters and acetylcholine receptors, our nanocapsules traverse the BBB with ease to proceed with treatment.
Crossing the BBB was only the beginning of an undertaking in which we sought to engineer an effective antibody-based treatment for cancerous metastases to the CNS; gaining the ability to deliver these nanocapsules successfully then brought us to the complexities of specific delivery. This matter is twofold, the first concern being the integrity of our nanocapsule’s shell. With a desire for seemingly contrasting capabilities—environment-discerning and slowly degraded in physiological conditions, yet capable of quick release—our options for surface composition were limited. The group tinkered with numerous hydrolysable crosslinkers and a range of crosslinker ratios until an ideal composition was obtained: glycerol dimethacrylate, which degrades at acidic conditions but not at physiological conditions, coupled with 50% poly(lactide)-b-poly(ethylene glycol)-b-poly(lactide)-diacrylate triblock copolymer, which degrades at both conditions—a combination which allows the capsule to rapidly release encapsulated antibodies in the acidic microenvironment surrounding a tumor yet slowly degrade in body fluids, providing enough time to circulate throughout the entire body. With this composition, our nanocapsules preferentially release antibodies when in close proximity to cancerous cells—eliminating concerns of untimely release.
The second concern regards specific targeting of cancerous cells; directionless circulation leads to poor accumulation in organs bearing tumors, rendering our nanocapsule-based treatment ineffective. As a model cancer, we first established a human B-cell lymphoma line which aggressively metastasizes to the CNS of mice. Then, the decisive tactic used to address specific delivery of our nanocapsules to target B-cell lymphomas was surface conjugation of the ligand CXCL13: a chemokine that interacts with CXCR5 on B cells. We tested the platform’s efficacy in a murine model through hours of in vivo bioluminescent imaging on the IVIS Spectrum system; with this instrument, tumor progression and regression alike were captured and tracked over a period of months to deliver the results we present to you in our paper, “Sustained delivery and molecular targeting of a therapeutic monoclonal antibody to metastases in the central nervous system of mice”. A single dose of CXCL13-conjugated nanocapsules led to improved control of B-cell lymphoma with CNS metastases in a murine xenograft and eliminated lymphoma in a xenografted humanized bone-marrow–liver–thymus mouse model.
The beauty of this nanocapsule-based treatment platform lies in its remarkable simplicity—the resultant ministration and its machinations are easily explained to treatment recipients. In a way, this marked simplicity is a great metaphor for our approach in developing immunological advances: with intent to refine translational medicine to the point that making a therapy “bench-to-bedside” is as easy as wrapping up the ideal treatment in the right packaging and delivering it to a patient in need.
Our paper: Wen J., Wu D., Qin M., Liu C., Wang L., Xu D., Vinters H.V., Liu Y., Kranz E., Guan X., Sun G., Sun X., Lee Y., Maza O.M, Widney D., Lu Y, Chen I.S.Y, and Kamata M. Sustained delivery and molecular targeting of a therapeutic monoclonal antibody to metastases in the central nervous system of mice. Nature Biomedical Engineering; https://doi.org/10.1038/s41551-019-0434-z
By Emiko Kranz (Research Associate, UCLA)
The UCLA AIDS Institute has been a place of learning and growth for me in the last 6 years under Dr.Masakazu Kamata; having the opportunity to contribute to tremendous progress, spearheaded by scientists who I am honored to work with, makes every experiment-filled minute of my day worthwhile.