Synthesis and Relaxometric Studies of a Dendrimer‐Based pH‐Responsive MRI Contrast Agent

Abstract

The design of effective pH responsive MRI contrast agents is a key goal in the development of new diagnostic methods for conditions such as kidney disease and cancer. A key factor determining the effectiveness of an agent is the difference between the relaxivity of the "on" state compared to that of the "off" state. In this paper, we demonstrate that it is possible to improve the pH-responsive action of a low molecular weight agent by conjugating it to a macromolecular construct. The synthesis of a bifunctional pH responsive agent is reported. As part of that synthetic pathway we examine the Ing-Manske reaction, identifying an undesirable by-product and establishing effective conditions for promoting a clean and effective reaction. Reaction of the bifunctional pH responsive agent with a G5-PAMAM dendrimer yielded a product with an average of 96 chelates per dendrimer. The relaxivity of the dendrimer conjugate rises from 10.8 mM(-1) s(-1) (pH 9) to 24.0 mM(-1) s(-1) (pH 6) per Gd(3+) ion. This more than doubles the relaxivity pH response, Deltar(1), of our agent from just 51 % for the original low molecular weight chelate to 122 % for the dendrimer.

Degradable Dual pH‐ and Temperature‐Responsive Photoluminescent Dendrimers

“…[8] A gadolinium complex conjugated to a dendrimer has been found to display pH-dependent relaxivity in magnetic resonance imaging, this parameter varying from 10.8 mm À1 s À1 per Gd 3 + ion at pH 9 to 24.0 mm À1 s À1 per Gd 3 + ion at pH 6. [9,10] Moreover, it has been reported that N-isopropylacrylamide (NIPAM)-bearing dendrimers show marked differences in their transition enthalpies, hydrophobicities, and sensitivities to urea compared with the corresponding linear polymers. [11] PAMAM dendrimers have been shown to be capable of carrying and releasing two types of drugs in a controlled manner.…”

“…[11] PAMAM dendrimers have been shown to be capable of carrying and releasing two types of drugs in a controlled manner. [12] Therefore, stimuliresponsive dendrimers offer a unique platform for many applications, [6,13] particularly biomedical engineering in developing intelligent devices that are able to sense biosignals or microenvironments, [14] such as tumor-sensitive contrast agents, [9,15] tumor-targeted drug release carriers, [16,17] and gene delivery carriers. [18] Dual responses to both temperature and pH offer two parameters for manipulating nanocarriers so as to achieve better targeting and efficacy in complicated microenvironments [19] or for other functions such as triggered release.…”

Dendrimer-based magnetic resonance imaging agents for brain cancer

“…Sherry and colleagues [60] further reported that the relaxivity and responsiveness of Gd-DOTA-4AmP 5− was improved by conjugation to a PAMAM dendrimer (Fig. 15b), which generated nanoparticles with~96 pH-responsive Gd 3+ -chelates.…”

“…Also, protonated dendrimers often generate a more rigid and open structure, and hence a further increase in relaxivity [58,59]. Moreover, Ali and colleagues [60] reported a pHsensitive agent based on a PAMAM dendrimer of generation 5 which bears a DOTA-derived chelating ligand, DOTA-4AmP, at the dendrimer surface. The relaxivity of this agent was more than doubled when the pH was changed from 9 to 6.…”

Smart MR Imaging Agents Relevant to Potential Neurologic Applications

“…Recently, the amplitude of the relaxivity response to pH variation of this low-molecularweight probe has been largely improved (more than doubled) by conjugating it to a macromolecular dendrimeric scaffold. 59 However, improving the relaxivity response to pH through increased molecular weight may also negatively impact the effectiveness of such agents. Large molecules, such as dendrimers, remain in the vasculature longer than discrete agents, which are better able to diffuse into all extracellular space.…”