Nmr contrast enhancement of brain tumours: comparison of the blood brain barrier tracer GdDTPA and the tumour-selective contrast agent MnTPPS

Contrast enhancement of two different NMR contrast agents, GdDTPA and MnTPPS, was compared. Sequential recording ofT ₁-weighted images at 50s intervals allowed the observation of the temporal and spatial evolution of the contrast effect in rats with glioma implanted into the right brain hemisphere. The maximum signal intensity ratio of tumour over contralateral striatum was 1.80±0.10 for GdDTPA and 1.61±0.15 for MnTPPS. The enhancement was maximal 3min after application of GdDTPA and fell rapidly to reach half maximum after 24 min. MnTPPS led to maximum tumour enhancement within 11 min and did not return to control level within the observation period (150 min). In the peritumoural edema, an enhancement effect was absent for MnTPPS, but GdDTPA spread out from the tumour resulting in a delayed but strong enhancement outside the tumour. Thus, GdDTPA, as a blood-brain-barrier tracer, led only to a transient contrast enhancement between tumour and surrounding tissue and no unambiguous demarcation of the tumour against peritumoural edema. Application of MnTPPS resulted in a long-lasting strong tumour enhancement and reliable delineation from peritumoural edema.     

Complexing the Oncolytic Adenoviruses Ad∆∆ and Ad-3∆-A20T with Cationic Nanoparticles Enhances Viral Infection and Spread in Prostate and Pancreatic Cancer Models

Oncolytic adenoviruses (OAd) can be employed to efficiently eliminate cancer cells through multiple mechanisms of action including cell lysis and immune activation. Our OAds, AdΔΔ and Ad-3∆-A20T, selectively infect, replicate in, and kill adenocarcinoma cells with the added benefit of re-sensitising drug-resistant cells in preclinical models. Further modifications are required to enable systemic delivery in patients due to the rapid hepatic elimination and neutralisation by blood factors and antibodies. Here, we show data that support the use of coating OAds with gold nanoparticles (AuNPs) as a possible new method of virus modification to help augment tumour uptake. The pre-incubation of cationic AuNPs with AdΔΔ, Ad-3∆-A20T and wild type adenovirus (Ad5wt) was performed prior to infection of prostate/pancreatic cancer cell lines (22Rv, PC3, Panc04.03, PT45) and a pancreatic stellate cell line (PS1). Levels of viral infection, replication and cell viability were quantified 24–72 h post-infection in the presence and absence of AuNPs. Viral spread was assessed in organotypic cultures. The presence of AuNPs significantly increased the uptake of Ad∆∆, Ad-3∆-A20T and Ad5wt in all the cell lines tested (ranging from 1.5-fold to 40-fold), compared to virus alone, with the greatest uptake observed in PS1, a usually adenovirus-resistant cell line. Pre-coating the AdΔΔ and Ad-3∆-A20T with AuNPs also increased viral replication, leading to enhanced cell killing, with maximal effect in the most virus-insensitive cells (from 1.4-fold to 5-fold). To conclude, the electrostatic association of virus with cationic agents provides a new avenue to increase the dose in tumour lesions and potentially protect the virus from detrimental blood factor binding. Such an approach warrants further investigation for clinical translation.