Noninvasive Monitoring of HPMA Copolymer–RGDfK Conjugates by Magnetic Resonance Imaging

Abstract

Purpose-To evaluate the tumor targeting potential of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-gadolinium(Gd)-RGDfK conjugates by magnetic resonance (MR) T1-mapping.Methods-HPMA copolymers with and without RGDfK were synthesized to incorporate side chains for Gd chelation. The conjugates were characterized by their side-chain contents and r 1 relaxivity. In vitro integrin-binding affinities of polymeric conjugates were assessed via competitive cell binding assays on HUVEC endothelial cells and MDA-MB-231 breast cancer cells. In vivo MR imaging was performed on MDA-MB-231 tumor-bearing SCID mice at different time points using non-targetable and targetable polymers. The specificity of αvβ3 targeting was assessed by using nonparamagnetic targetable polymer to block αvβ3 integrins followed by injection of paramagnetic targetable polymers after 2 h.Results-The polymer conjugates showed relaxivities higher than Gd-DOTA. Endothelial cell binding studies showed that IC 50 values for the copolymer with RGDfK binding to αvβ3 integrinpositive HUVEC and MDA-MB-231 cells were similar to that of free peptide. Significantly lower T1 values were observed at the tumor site after 2 h using targetable conjugate (p<0.012). In vivo blocking study showed significantly higher T1 values (p<0.045) compared to targetable conjugate.Conclusion-These results demonstrate the potential of this conjugate as an effective targetable MR contrast agent for tumor imaging and therapy monitoring.

Gold nanorod-mediated hyperthermia enhances the efficacy of HPMA copolymer-90Y conjugates in treatment of prostate tumors

“…The purified copolymer was obtained by lyophilization and analyzed by Fast Protein Liquid Chromatography (FPLC) system (GE Healthcare, Piscataway, NJ) equipped with a multi-angle light scattering (MALS) detector (Wyatt Technologies, Santa Barbara, CA). DOTA content was determined by analyzing gadolinium content (assuming a 1:1 ratio) after chelation according to previously described methods [21]. …”

Investigation into the Biological Impact of Block Size on Cathepsin S-Degradable HPMA Copolymers

“…11–14 Despite the increased tumor targeting capabilities of larger, longer-circulating HPMA copolymers, much of the reported SPECT or PET agent development to date has centered on the utilization of HPMA copolymers that are lower than the renal excretion threshold, ~ 45 kDa, to limit MPS uptake and retention. Our laboratory has been investigating the exploitation of a protease, Cat S, which is highly expressed in the phagocytic cells constituting the MPS in order to lower the non-target retention of radiolabeled polymeric drug carriers.…”

Comparison of Active and Passive Targeting of Docetaxel for Prostate Cancer Therapy by HPMA Copolymer–RGDfK Conjugates

“…They have also been reported to be tumor penetrating and its coadministration enhances the efficacy of anticancer drugs 47 . Compared to non-targeted systems, previous investigations in our laboratory 48–52 have identified actively targeted HPMA copolymer–cyclo-RGD conjugates that increase tumor accumulation. This accumulation takes place through specific interaction of RGD motifs present in the copolymer side chains with α v β 3 integrins overexpressed on both angiogenic blood vessels 37 and a variety of tumor cells including prostate cancer 53 .…”