pH-Dependent Cellular Internalization of Paramagnetic Nanoparticle

A hallmark of the tumor microenvironment in malignant tumor is extracellular acidosis, which can be exploited for targeted delivery of drugs and imaging agents. A pH sensitive paramagnetic nanoaparticle (NP) is developed by incorporating GdDOTA-4AmP MRI contrast agent and pHLIP (pH Low Insertion Peptide) into the surface of a G5–PAMAM dendrimer. pHLIP showed pH-selective insertion and folding into cell membranes, but only in acidic conditions. We demonstrated that pHLIP-conjugated Gd₄₄-G5 paramagnetic nanoparticle binds and fuses with cellular membrane at low pH, but not at normal physiological pH, and that it promotes cellular uptake. Intracellular trafficking of NPs showed endosomal/lysosomal path ways

Comparison of TIFP distribution as a function of position (depth) at steady state for various <i>β</i>.

<p>Other parameters are the same based on <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140892#pone.0140892.e026" target="_blank">Eq 18</a> in appendix.</p

Schematic for determining the unit length in mm per pixel.

<p>Schematic for determining the unit length in mm per pixel.</p

The average gray-value of the rim of tumor 1 in liver 1 in different directions at various times.

<p>The average gray-value of the rim of tumor 1 in liver 1 in different directions at various times.</p

Comparison of our model for ‘embedded’ tumors with the experimental data from Figs 3A track 5 (lower) and 6 track 4 (upper, which represents approximately the average value of all readings from all tracks) in Ref. 1.

<p>The readings from these two tracks are distributed across all regions of the tumors.</p

The slope of <i>u</i>(<i>R</i>_s)~<i>p</i>₀ for various tumors and contrast agents.

<p>The slope of <i>u</i>(<i>R</i>_s)~<i>p</i>₀ for various tumors and contrast agents.</p

Comparison of the model for an ‘isolated’ tumor based on Eq 4 with the experimental data from Fig 8 in Ref. 1.

<p>Only three parameters are needed and they are measurable.</p

Schematic of fluid flow in the regions close to tumour surface.

<p>A tumour boundary can be chosen so that it is locally one-dimensional (the figure on the left is from Fig 2B-4 in Ref. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140892#pone.0140892.ref007" target="_blank">7</a>; it shows a T1-weighted MRI image of a TS-415 cervical carcinoma). <i>S</i> represents the base of the fluid flux in the local coordinate system in which a 1D model can be applied.</p

Liver tumors with a contrast enhancing rim visible.

<p>Several measurements of the rim were made along tumor periphery to infer TIFP. A judicious local coordinate system may be chosen, in which a 1D model can be applied. The rim of tumor 1 in liver 1 is approximately 3.2 mm in 4 pixels, ~0.8mm/pixel.</p

The average gray-value of the rim of tumor 2 in liver 1 in different directions at various times.

<p>The average gray-value of the rim of tumor 2 in liver 1 in different directions at various times.</p