Acid-mediated Lipinski's second rule: application to drug design and targeting in cancer

Abstract

With a predicted 382.4 per 100,000 people expected to suffer from some form of malignant neoplasm by 2015, and a current death toll of 1 out of 8 deaths worldwide, improving treatment and/or drug design is an essential focus of cancer research. Multi-drug resistance is the leading cause of chemotherapeutic failure, and delivery of anticancer drugs to the inside of cancerous cells is another major challenge. Fifteen years ago, in a completely different field in which improving drug delivery is the objective, the bioavailability of oral compounds, Christopher Lipinski formulated some rules that are still used by the pharmaceutical industry as rules of thumb to improve drug delivery to their target. Although Lipinski's rules were not formulated to improve delivery of antineoplastic drugs to the inside of cancer cells, it is interesting to note that the problems are similar. On the basis of the strong similarity between the fields, we discuss how they can be connected and how new drug targets can be defined in cancer.

Fig. 1

The lipid number asymmetry-induced fluid phase endocytosis model. Schematic diagram of the current model applied to living cells which links fluid phase endocytosis and membrane phospholipid number asymmetry maintained by a flippase. In the left figure, the translocation of dark-head lipids into the inner leaflet induces differential lipid packing between leaflets (different surface tension) leading to membrane bending and vesiculation (Farge et al. ; Rauch and Farge 2000b). Note that it is assumed that the membrane recycling that occurs in cells, i.e. the exocytosis of vesicles of a size similar to endocytic vesicles, also enables maintenance of lipid asymmetry at the level of the plasmalemma. The relationship between lipid number asymmetry and the vesicle radius is given by $R=8k_c/h\mathrm{\Delta }\mathit{\sigma }$ or, equivalently, $R=4k_c/hK·1/(\mathit{\delta }N/N_0)$, where $k_c$, $K$, $h$, $\mathrm{\Delta }\mathit{\sigma }$ and $\mathit{\delta }N/N_0$ are the membrane bending modulus, membrane elastic modulus, membrane thickness, surface tension difference, and the lipid number asymmetry between leaflets. Accordingly, lipid number asymmetry has been experimentally deduced from studies on cells for which $\mathit{\delta }N/N_0=2\pm 0.5\%$ providing a ~35 nm vesicle radius (Rauch and Farge 2000b)

Fig. 2

a Relationship between drugs’ MW and their ability to bypass the membrane barrier as a function of vesicle radius $R(\text{nm})$ expressed in nanometers, scaling as ${\text{MW}}_c\sim R^{3/2}$ (exactly: ${\text{MW}}_c\cong 1.1R^{3/2}$using constants seen in the text)

Fig. 3

Effect of pH on the packing of lipids. a Assuming a leaflet composed of charged lipids. The optimum area per lipid is determined by the competition between energy that reflects lipids attraction linked to their hydrophobic tails and repulsion energy which we will assume to be linked to a net charge carried by all lipids. The competition between these two terms defines an energy minimum. Note that in the figures r ₀ corresponds to the optimum distance between adjacent lipid heads. b Thus the minimum energy determines the optimum distance between lipids, including their optimum area in the monolayer. Note that the packing of lipids is not always defined by physical contact and that, accordingly, there is room to change this packing. c With regard to negatively charged lipids, an increase in the concentration of hydrogen ions enables more hydrogen ions to interact with lipids’ heads. Thus, by masking their negative charge, the long-range repulsion between lipids is disturbed. The resulting effect will be alteration of the positioning of the energy minimum, so the lipids become closer. d Top view of a portion of the membrane. The lipid’s head is colored in red and the optimum area per lipid driven by repulsive and/or attractive interactions is drawn in blue. Changes in pH are expected to redefine the optimum area per lipid, and thus their packing. In the figure a decrease in the pH is represented, i.e. pH₂ < pH₁. In conclusion, a low cytosolic pH is expected to reduce the surface area per lipid. Lipids should have more room, thus reducing their packing. Changing the cytosolic pH is thus expected to affect the packing of inner leaflet lipids because it is in this leaflet that negatively charged lipids are found. To conclude, the packing of lipids can vary even though the number of lipids is unchanged. In this case, pH-driven alteration of lipid repulsion causes this change. Accordingly, this change is expected to affect the transverse movement of drugs across the membrane and thus their efficacy, as demonstrated by Rauch (2009b)

Fig. 4

Acid-induced drug release from pH-responsive micelles