Contrast-Enhanced MRI-Guided Photodynamic Cancer Therapy with a Pegylated Bifunctional Polymer Conjugate

Abstract

Purpose-To study contrast-enhanced MRI guided photodynamic therapy with a pegylated bifunctional polymer conjugate containing an MRI contrast agent and a photosensitizer for minimally invasive image-guided cancer treatment.Methods-Pegylated and non-pegylated poly-(L-glutamic acid) conjugates containing mesochlorin e 6 , a photosensitizer, and Gd(III)-DO3A, an MRI contrast agent, were synthesized. The effect of pegylation on the biodistribution and tumor targeting was non-invasively visualized in mice bearing MDA-MB-231 tumor xenografts with MRI. MRI-guided photodynamic therapy was carried out in the tumor bearing mice. Tumor response to photodynamic therapy was evaluated by dynamic contrast enhanced MRI and histological analysis.Results-The pegylated conjugate had longer blood circulation, lower liver uptake and higher tumor accumulation than the non-pegylated conjugate as shown by MRI. Site-directed laser irradiation of tumors resulted in higher therapeutic efficacy for the pegylated conjugate than the nonpegylated conjugate. Moreover, animals treated with photodynamic therapy showed reduced vascular permeability on DCE-MRI and decreased microvessel density in histological analysis.Conclusions-Pegylation of the polymer bifunctional conjugates reduced non-specific liver uptake and increased tumor uptake, resulting in significant tumor contrast enhancement and high therapeutic efficacy. The pegylated poly(L-glutamic acid) bifunctional conjugate is promising for contrast enhanced MRI guided photodynamic therapy in cancer treatment.

Targeted intracellular codelivery of chemotherapeutics and nucleic acid with a well-defined dendrimer-based nanoglobular carrier

“…Liposomes have a relatively large payload, but formulation of liposomal delivery systems is relatively complicated and the surface of liposomes needs to be modified with biocompatible polymers to minimize non-specific tissue uptake [8]. Synthetic biocompatible macromolecules can accommodate different therapeutic agents for codelivery, but most of the synthetic macromolecules are mixtures of polymers of different sizes and do not have uniform and constant morphology before and after chemical modifications, which may complicate their pharmacokinetic properties during in vivo applications [9].…”

Are nanotheranostics and nanodiagnostics-guided drug delivery stepping stones towards precision medicine?

“…In fact, an example that highlights this property is a comparison of PEGylated poly(Lglutamic acid) containing mesochlorin e6, a photosensitizer, and Gd(III)-DO3A (PGA-(Gd-DO3A)-Mce6) to the non-PEGylated particles where the PEGylated system revealed reduced signal from the liver. This was accompanied by higher intensity signal from the tumor at 18 hr after treatment (Vaidya et al, 2008). These aforementioned examples for the enhancement in SNR are presented in Figure 2. …”

Approaches in the Chemoprevention of Breast Cancer

“…PG conjugated with gadolinium chelate (PG-DTPA-Gd) has been developed as an MRI Citation: Dileep KV, Kelly M, Hardin E, Sadasivan C, Nair HB (2013) Approaches in the Chemoprevention of Breast Cancer. J Cancer Sci Ther 5: 282-288. doi:10.4172/1948-5956.1000217 Volume 5(8) [42]. This group demonstrated that PG-DTPA-Gd would be degraded by cysteine proteases within 24h in the presence of cathepsin B. Li's group further developed this PG-DTPA-Gd and demonstrated that these agents will accumulate in the necrotic tissue of the tumor due to its co localization with macrophages.…”

“…The ideal polymeric contrast agents in the diagnostics will have minimal or no toxicity because they degrade and clear from the body after the imaging is completed Poly L-glutamic acid (PG) is well known for its biocompatibility, biodegradability, and water solubility [41]. PG conjugated with gadolinium chelate (PG-DTPA-Gd) has been developed as an MRI contrast agent [42]. This group demonstrated that PG-DTPA-Gd would be degraded by cysteine proteases within 24h in the presence of cathepsin B. Li's group further developed this PG-DTPA-Gd and demonstrated that these agents will accumulate in the necrotic tissue of the tumor due to its co localization with macrophages.…”