Plant Viruses for the Delivery of Platinum Anticancer Therapeutics
Platinum-based anticancer drugs such as cisplatin, carboplatin, and oxaliplatin are used in the treatment of nearly half of the population of the cancer patients undergoing chemotherapy. These drugs, however, lack selectivity and have dose-limiting toxicities, low bio-availability, rapid clearance from the body, and may encounter drug resistance mechanisms, leading to the recurrence of the cancer. Therefore, efficient loading of drugs in novel delivery agents has the potential to substantially improve therapy by directly targeting the diseased tissue and avoiding unwanted side effects. Given that the development of new drugs is expensive, reducing toxicity caused by existing drugs by packaging them into delivery vehicles is attractive and can be achieved by controlled and targeted methodologies. Although presently available nano-sized delivery agents impart safety, their limited efficacy and inability to penetrate tissue adequately are some of the limitations. Consequently, development of new drug delivery methods has been a subject of recent burgeoning interest.
Viruses are very simple in structure and composition, and they can be considered as biology-derived nanocarriers, naturally evolved to carry and delivery cargos to target cells. Moreover, they can transfect host cells with a very high efficiency. However, their immunogenic nature hinders their development as drug carriers. In this regard, plant viruses form an emerging platform technology as they offer several advantages over mammalian vectors.
In this talk, I will highlight the use of tobacco mosaic virus (TMV) for the delivery of platinum anticancer therapeutics. It has been shown previously by our research group that the highly potent analogues of cisplatin, phenanthriplatin (1) and its aqua-form (2), are differentially taken up in the TMV channel. Whereas ~1000 molecules of 1 are loaded in TMV, 2 is taken up in higher quantities (~2000 molecules per TMV particle). Studies on delineating the mechanism of their differential uptake and their stabilization in the TMV channel will be discussed in detail. Furthermore, I will also discuss on the heat-transition of TMV nanorods to nanospheres (SNPs) in the presence of 1, which leads to significant uptake of 1 in the bulk of SNPs, and their mechanism of formation. These SNPs are stable in the fetal bovine serum (FBS) medium and they do not release 1 at pH 7.4 and pH 5, which may further prevent the toxicity arising due to off-target release of drugs. To an added advantage, the release of 1 is only triggered by proteolytic enzyme like trypsin which is a constituent of endosome. SNP delivery system presents a comparable to better anticancer efficacy in the panel of cancer cell lines. These investigations inform the design of future drug analogues that can be efficiently encapsulated, stabilized in different morphologies of TMV, and delivered to the tumor site.
1.A. E. Czapar, Y. Zheng, I. A. Riddel, S. Shukla, S. G. Awuah, S. J. Lippard, N. F. Steinmetz, ACS Nano, 2016, 10, 4119-4126.
2.A. A. Vernekar, G. Berger, A. E. Czapar, F. A. Veliz, D. Wang, N. F. Steinmetz, S. J. Lippard, J. Am. Chem. Soc., 2018, 140, 4279-4287.
3.A. A. Vernekar, F. A. Veliz, N. F. Steinmetz, S. J. Lippard, (SNP work will be submitted soon).