Cancer nanomedicines: so many papers and so few drugs!

Abstract

This review identifies a timeline to nanomedicine anticancer drug approval using the business model of inventors, innovators and imitators. By evaluating the publication record of nanomedicine cancer therapeutics we identified a trend of very few publications prior to FDA approval. We first enumerated the publications related to cancer involving polymers, liposomes or monoclonal antibodies and determined the number of citations per publication as well as the number of published clinical trials among the publications. Combining these data with the development of specific nanomedicines, we are able to identify an invention phase consisting of seminal papers in basic science necessary for the development of a specific nanomedicine. The innovation phase includes the first report, the development and the clinical trials involving that nanomedicine. Finally, the imitation phase begins after approval when others ride the wave of success by using the same formulation for new drugs or using the same drug to validate other nanomedicines. We then focused our analysis on nanomedicines containing camptothecin derivatives, which are not yet approved including two polymers considered innovations and one liposomal formulation in the imitation phase. The conclusion that may be drawn from the analysis of the camptothecins is that approved drugs reformulated in polymeric and liposomal cancer nanomedicines have a more difficult time navigating through the approval process than the parent molecule. This is probably due to the fact that for most currently approved drugs, reformulating them in a nanocarrier provides a small increase in performance that large pharmaceutical companies do not consider being worth the time, effort and expense of development. It also appears that drug carriers have a more difficult path through the clinic than monoclonal antibodies. The added complexity of nanocarriers also deters their use to deliver new molecular entities. Thus, the new drug candidates that might be most improved by drug delivery in nanocarriers are not formulated in this fashion.

Figure 1

Nanomedicine publication profiles over time. A: Polymeric cancer therapeutics, B: liposomal cancer therapeutics and C: monoclonal antibody therapeutics. Solid line: Number of publications per year, Dashed line: number of citations per year and Dotted line: number of published clinical trials per year.

Figure 2

Invention, innovation and imitation timeline overlapped on the plot of publications per year with seminal publications highlighted.

Figure 3

Polymer and liposomal cumulative publication profiles with small molecule drugs. A: Publication profile of polymer and liposomal therapeutics containing a camptothecin derivative and B: publication profile of polymer and liposomal therapeutics containing platinum. Black lines: Polymer publications, Grey lines: liposomal publications, Solid lines: all publications and Dotted lines: clinical trials.

Figure 4

Nanomedicine innovation and approval timeline. Blue arrows: Innovation phase, period from last invention to drug innovation; Red Arrows: Development phase, period from innovation to clinical trials; Green Arrows: Clinical trial phase, period from clinical trials to FDA decision. Lack of a blue arrowhead denotes concurrent innovation and clinical trials.