Poly(2-oxazoline) nanoparticle delivery enhances the therapeutic potential of vismodegib for medulloblastoma by improving CNS pharmacokinetics and reducing systemic toxicity

Abstract

We report a novel, nanoparticle formulation of the SHH pathway inhibitor vismodegib that improves efficacy for medulloblastoma treatment while reducing toxicity. Systemic therapies for brain tumors are complicated by restricted blood-brain barrier (BBB) permeability and doselimiting extraneural toxicity, therefore improved delivery approached are needed. Here we show how a nanoparticle delivery system addresses these obstacles, bringing new efficacy to previously ineffective therapy. Vismodegib has been a promising agent for patients with SHHsubgroup medulloblastoma and is FDA-approved for basal cell carcinoma. However, vismodegib has limited benefit for patients with SHH-driven medulloblastoma, due to off-target toxicities and the development of resistance during therapy. We encapsulated vismodegib in polyoxazoline block copolymer micelles (POx-vismo). We then evaluated POx-vismo using transgenic mice engineered to develop endogenous medulloblastomas, testing the novel agent in a preclinical model with native vasculature and tumor microenvironment. POx-vismo showed improved CNS pharmacokinetics and reduced systemic and bone toxicity. Mechanistic studies show that POx nanoparticles did not enter the CNS, but rather acted within the vascular compartment to improve drug delivery by decreasing drug binding to serum proteins and reducing the volume of distribution. POx-vismo demonstrated improved efficacy, extending the survival of medulloblastoma-bearing mice. Our results show the potential for a simple, non-targeted nanoparticle formulation to improve systemic brain tumor therapy, and specifically to enhance vismodegib therapy for SHH-driven cancers.

Enhancing CDK4/6 inhibitor therapy for medulloblastoma using nanoparticle delivery and scRNA-seq-guided combination with sapanisertib

“…The resulting G-Smo mice developed medulloblastoma with 100% penetrance by P10 and, untreated, died of progressive tumors by P20, as in prior studies (16)(17)(18)(19). Consistent with the previously reported data, oral dosing or systemic dosing of free palbociclib (Palbo-HCl) didn't induce survival benefits.…”

“…We first attempted to load palbociclib into the POx-A, hydrophilic, non-charged A-B-A type copolymer, (P[MeOx34-b-BuOx20-b-MeOx35] (Mn = 8.6 kg/mol)) that we previously used to formulate vismodegib (16). However, the loading capacity of palbociclib in POx-A was very low (Fig.…”

“…For non-water soluble drugs (vismodegib, etoposide, sapanisertib) we have developed POx based micellar formulation, building upon previous data that loading drugs into POx micelles reduces toxicity and improves efficacy of treatment. Our prior studies showed that vismodegib administered systemically to G-Smo mice in polyoxazoline nanoparticles (POx-Vismo) was more effective for medulloblastoma therapy than conventional vismodegib (16). We previously developed a formulation of etoposide loaded into POx micelles (POx-Etop) and showed that this formulation was less toxic and more effective than free drug in a mouse lung cancer models (30,31).…”

“…POx delivery of the SHH inhibitor vismodegib increases brain and tumor drug exposure, reduces systemic toxicity and providing increased efficacy (16). Based on these prior studies, we tested whether POx delivery improved palbociclib efficacy.…”

Poly(2-ethyl-2-oxazoline-co-N-propylethylene imine)s by controlled partial reduction of poly(2-ethyl-2-oxazoline): synthesis, characterization and cytotoxicity

“…Poly(2-oxazoline)s as a very diverse polymer family have seen a tremendous increase of interest for the preparation of biomaterials. 37 Recent years have seen the first-in-man clinical trials for POxbased polymer drug conjugates 38 , very significant advances in preclinical studies of POx based micellar drug delivery systems [39][40][41][42][43][44][45][46][47][48] , and hydrogels for various biomedical applications. [49][50][51][52][53] The presented results add another layer of chemical versatility to this already multifarious polymer family, which are particular interesting potential application for the complexation of oppositely charged biomacromolecules such as proteins and polynucleic acids.…”