Novel prodrugs for targeting diagnostic and therapeutic radionuclides to solid tumors

Abstract

Most cancer therapeutics (chemo, radiation, antibody-based, anti-angiogenic) are at best partially and/or temporarily effective. In general, the causes for failure can be summarized as: (i) poor diffusion and/or nonuniform distribution of drug/prodrug molecules in solid tumors; (ii) high drug concentration and retention in normal tissues (leading to side effects); (iii) requirement for plasma-membrane permeability and/or internalization of drug/prodrug molecules; (iv) low uptake of drug by tumor; (v) lack of retention of drug within tumor (most have gradient-driven reversible binding); and (vi) multidrug resistance. We are developing an innovative technology that aims to surmount these problems by actively concentrating and permanently entrapping radioimaging and radiotherapeutic prodrugs specifically within solid tumors. The approach will enable noninvasive sensing (imaging) and effective therapy of solid tumors, allowing tumor detection, diagnosis, and treatment to be closely coupled (personalized medicine).

Figure 1

Schematic diagram of EMCIT technology.

Figure 2

In silico docking positions of IQ_2–P in active site of AP.

Figure 3

Structure and water solubility of iodinated quinazolinone derivatives.

Figure 4

Hydrolysis of ¹²⁵IQ_2–P following 5-min incubation in AP or PAP at various pH values, indicating that dephosphorylation is favored at lower pH.

Figure 5

Fluorescence microscopy of viable human TE671 rhabdomyosarcoma cells incubated (37^oC) in vitro (pH 7.4) with IQ_2–P analogs, showing hydrolysis and crystallization of these derivatives (green). Note different size and intensity of crystals formed. (A, C, and E) low power – cells not washed. (B, D, and F) high power –cells washed with PBS, fixed in methanol, and nuclei counterstained with DAPI (blue).

Figure 6

Fluorescence microscopy of viable human T3M4 pancreatic tumor cells incubated (37^oC) in vitro with IQ_2–P in media at varying pH, showing that prodrug is hydrolyzed more efficiently and more rapidly at pH 6.5. Columns 1–3: low power – cells not washed; column 4: high power – cells washed with PBS, fixed in methanol, and nuclei counterstained with DAPI.

Figure 7

T/NT ratios in mice bearing i.p. OVCAR-3 tumors and injected i.p. 24 h earlier with ¹²⁵IQ_2–P.