(141c) Nanoparticle Delivery Doubles the Antinociception Effect of a CGRP Receptor Antagonist in Oral Cancer Pain Models

Affecting 30,000 Americans annually, oral cancers are difficult to treat with a modest 50% 5-year survival rate¹. Oral cancers are extremely painful with increasing pain as the disease progresses². It is well established that the majority of cancer pain is initiated at the tumor site³. Pressingly, the therapeutic options to treat cancer pain are limited to opioids, which have profound drawbacks, including sedation, respiratory depression, nausea, constipation, tolerance and dependence^{4, 5}. As an alternative to opioids, we target the calcitonin gene-related peptide (CGRP) receptors on cancer cells, which are implicated in cancer pain signaling. Due to the leaky vasculature and enhanced lymphatic drainage characteristic of oral cancers, maintaining drug concentrations in the tumor microenvironment (TME) is challenging⁶. This limits the duration of efficacy of free small molecule CGRP antagonists. Our goal is to enhance the duration and intensity of analgesia by using CGRP antagonist loaded nanoparticles, which (1) are better retained in the TME due to their large size (100 nm) compared to small molecule drugs (10 Å) and (2) can be designed for sustained drug release.⁷

Methods:

The CGRP antagonists olcegepant was encapsulated into PLA-PEG nanoparticles using the Flash NanoPrecipitation (FNP) process, in which nanoparticles are assembled via diffusion limited self-assembly driven by hydrophobic interactions. The hydrophobic ion pairing (HIP) nanoformulation approach was used to control the olcegepant release rate. Nanoparticles were characterized by standard physicochemical characterization techniques. To test antinociception in vivo, a human squamous cell carcinoma (HSC-3) cancer xenograft paw and tongue model were used. After the mice developed cancer nociception, the mice were injected with either with free olcegepant (500 nM) or olcegepant-loaded nanoparticle (500 nM). Saline and empty NPs served as controls. To measure cancer nociception development in paw or tongue and to determine the treatment efficacy, we used the von Frey filament and Hargreaves assays for mechanical and thermal allodynia, respectively.

Results:

Olcegepant was successfully encapsulated into 100 nm PLA-PEG nanoparticles using the HIP nanoformulation approach with pamoic acid as the counter ion. Nanoparticles had an olcegepant drug loading of 5 wt%. The olcegepant FNP encapsulation efficiency was 60%. The nanoparticles exhibited a slow drug release rate with 80% drug release after 24 hours. In the cancer paw model, free olcegepant reduced 75% mechanical and 50% thermal cancer nociception for 6 hours post-administration. The olcegepant-loaded NPs-loaded reduced 98% mechanical and 100% thermal cancer nociception for 12 hours post-administration with a persistent reduction in pain lasting up to 24 hours.

Implications:

Inhibiting CGRP receptor signaling is a promising approach for the treatment of cancer pain. By using a nanoparticle drug delivery approach to deliver olcegepant in the TME, the duration and intensity of antinociception can be dramatically increased. This opens up a new avenue beyond opioids for cancer pain therapeutics.

References:

1. Sciubba, J. J., American Journal of Clinical Dermatology 2001, 2 (4), 239-251.
2. van den Beuken-van Everdingen, M. H et al.,. Ann Oncol 2007, 18 (9), 1437-49.
3. Kolokythas, A.; et al., J Pain 2007, 8 (12), 950-3.
4. Bruera, E.; Kim, H. N., Jama 2003, 290 (18), 2476-2479.
5. Mercadante, S., Cancer 1999, 86 (9), 1856-1866.
6. Sato, S., et al., JCI Insight 2019, 4 (23).
7. Ashton, S., et al., Science Translational Medicine 2016, 8 (325), 325ra17.