Tobacco mosaic virus delivery of mitoxantrone for cancer therapy.

Mitoxantrone (MTO) is a topoisomerase II inhibitor which has been used to treat various forms of cancer either as a solo chemotherapy regimen or as a component in cocktail treatments. However, as with other anti-neoplastic agents, MTO has severe cardiac side effects. Therefore, a drug delivery approach holds promise to improve the safety and applicability of this chemotherapy. Here, we report the application of a plant virus-based nanotechnology derived from tobacco mosaic virus (TMV) as a delivery vehicle for MTO towards cancer therapy. TMV is a high aspect-ratio, soft-matter nanotube with dimensions of 300 × 18 nm and a 4 nm wide channel. The surface chemistry of the interior and exterior TMV surfaces is distinct and we established charge-driven drug loading strategies to encapsulate therapeutics for drug delivery. We demonstrate effective MTO loading into TMV yielding ∼1000 MTO per TMV carrier. The treatment efficacy of MTO-loaded TMV (MTOTMV) was assessed in in vitro and in vivo models. In vitro testing confirmed that MTO maintained its efficacy when delivered by TMV in a panel of cancer cell lines. Drug delivery in vivo using a mouse model of triple negative breast cancer demonstrated the superior efficacy of TMV-delivered MTO vs. free MTO. This study demonstrates the potential of plant virus-based nanotechnology for cancer therapy and drug delivery.

Natural mutations in the receptor binding domain of spike glycoprotein determine the reactivity of cross-neutralization between palm civet coronavirus and severe acute respiratory syndrome coronavirus.

The severe acute respiratory syndrome (SARS) outbreak of 2002 and 2003 occurred as a result of zoonotic transmission. Coronavirus (CoV) found in naturally infected palm civet (civet-CoV) represents the closest genetic relative to SARS-CoV, but the degree and the determinants of cross-neutralization among these viruses remain to be investigated. Studies indicate that the receptor binding domain (RBD) of the SARS-CoV spike (S) glycoprotein contains major determinants for viral entry and neutralization. We aim to characterize the impact of natural mutations within the RBDs of civet-CoVs on viral entry and cross-neutralization. In this study, the S glycoprotein genes were recovered from naturally infected civets in central China (Hubei province), extending the geographic distribution of civet-CoV beyond the southeastern province of Guangdong. Moreover, pseudoviruses generated in our laboratory with four civet S genes, each with a distinct RBD, infected cells expressing human receptor angiotensin-converting enzyme 2, but with 90 to 95% less efficiency compared to that of SARS-CoV. These four civet S genes were also constructed as DNA vaccines to immunize mice. Immunized sera elicited against most civet S glycoproteins displayed potent neutralizing activities against autologous viruses but were much less efficient (50% inhibitory concentration, 20- to 40-fold) at neutralizing SARS-CoV and vice versa. Convalescence-phase sera from humans were similarly ineffective against the dominant civet pseudovirus. Our findings suggest that the design of SARS vaccine should consider not only preventing the reemergence of SARS-CoV but also providing cross-protection, thus interrupting zoonotic transmission of a group of genetically divergent civet CoVs of broad geographic origin.