Noninvasive Visualization of Pharmacokinetics, Biodistribution and Tumor Targeting of Poly[N-(2-hydroxypropyl)methacrylamide] in Mice Using Contrast Enhanced MRI

Wang, Yanli; Ye, Furong; Jeong, Eun Kee; Sun, Yongen; Parker, Dennis L.; Lü, Zheng Rong

doi:10.1007/s11095-007-9252-1

Cited by 46 publications

(34 citation statements)

References 27 publications

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“…Three-dimensional high-resolution dynamic contrast enhanced MRI is effective for noninvasive visualization of the real-time pharmacokinetics and biodistribution of the polymer conjugates in mouse tumor models (31)(32)(33). The MRI study revealed that PGA-(Gd-DO3A)-Mce 6 resulted in relatively short blood circulation and high liver uptake possibly due to the hydrophobic interaction of mesochlorin e 6 with the reticuloendothelial system.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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“…Detailed analysis on 2D spin-echo MR images of the tumor tissues showed that significant contrast enhancement was first observed at the tumor periphery post injection for all conjugates, and then gradually in the tumor interstitium, indicating that the distribution of the conjugates started at the tumor periphery and gradually diffused in the inner tumor tissue [27]. The 28-kDa conjugate had a short blood circulation time and its accumulation was limited to the tumor periphery.…”

Section: Mr Imaging Of Phpma-gflg-(gd-do3a) Conjugatesmentioning

confidence: 93%

“…Figure 1 shows that the pharmacokinetics of polymeric MRI contrast agents can be visualized by contrast enhanced MRI, which may also have a potential for noninvasive evaluation of pharmacokinetics of polymer drug conjugates. We have labeled N-(2-hydroxypropyl) methacrylamide copolymers (PHPMA) and poly(L-glutamic acid), two of the commonly used carriers for drug delivery, with a stable MRI contrast agent Gd-DO3A to explore the potential [27,28]. The structures of the conjugates are shown in Figure 2 and their physico-chemical characteristics are listed in Table 1.…”

Section: Non-invasive Visualization Of In Vivo Drug Delivery Of Polymmentioning

confidence: 99%

Polymer platforms for drug delivery and biomedical imaging

Lü

Vaidya

2007

Journal of Controlled Release

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Biocompatible synthetic polymers have demonstrated advantageous pharmacokinetic properties as compared to small molecular agents. Incorporation of low molecular weight therapeutics and imaging agents into biocompatible polymers can optimize their pharmacokinetic properties with improved efficacy of therapy and diagnostic imaging, respectively. We have applied the concept of drug delivery to design safe and effective contrast agents for magnetic resonance imaging (MRI) and used biomedical imaging in non-invasive evaluation of drug delivery and image-guided therapy. We summarize here the recent progress in our research on biodegradable macromolecular MRI contrast agents, non-invasive visualization of in vivo drug delivery of polymeric conjugates with contrast enhanced MRI, and contrast enhanced MRI guided photodynamic therapy. The preliminary results have shown that biocompatible polymers can be used as an effective platform for drug delivery and biomedical imaging. Safe and effective imaging agents can be designed by using the concept of polymeric drug delivery. Biomedical imaging can be used as a non-invasive method for the evaluation of in vivo drug delivery of polymeric drug delivery systems. The combination of drug delivery and biomedical imaging can result in image-guided therapies, which include tumor detection, therapy and non-invasive evaluation of therapeutic responses.Biocompatible and water-soluble polymers have demonstrated unique pharmacokinetic properties, including prolonged blood circulation and tissue retention, and preferential accumulation in lesions with blood vessel hyperpermeability, because of their large sizes. Biocompatible synthetic polymers have been used as a platform for the modification of pharmacokinetics of small molecular therapeutics and imaging agents to improve their efficacy in drug delivery and molecular imaging [1,2]. The conjugation of therapeutics to biocompatible polymers prolongs in vivo drug retention time, increases drug bioavailability, reduces systemic toxicity and enhances therapeutic efficacy [3,4]. The incorporation of imaging agents into biocompatible polymers prolongs their retention in the tissues of interest with increased concentrations, which allows more accurate disease detection and characterization [5,6]. For example, the incorporation of a magnetic resonance imaging (MRI) contrast agent into a macromolecule would increase its blood circulation time for effective contrast enhanced cardiovascular imaging and tumor imaging [7,8].Both drug delivery and molecular imaging can benefit from the large sizes and unique pharmacokinetic properties of biomedical polymers. However, the applications of biomedical polymers in these areas are not mutually exclusive. In fact, the concept of drug delivery can be applied in molecular imaging to design and develop effective and specific imaging agents Correspondence to: Dr. Zheng-Rong Lu, 421 Wakara Way, Suite 318, Salt Lake City, UT 84108, Phone: 801 587-9450, Fax: 801 585-3614, Email: E-mail: zhengrong.lu@utah.edu....

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“…The macromolecule or nanoparticulate MR contrast agents exhibited higher relaxivity owing to the slow tumbling of the macromolecules compared with that of low-molecularweight chelates. 2,48) In the in vivo MRI study, signal enhancement of T 1 -weighted images of the tumor area was observed 24 h after both NP and F(5000)-NP injection. Therefore, signal enhancement in tumor tissue would be facilitated by the high Gd concentration delivered by NPs to the tumor tissue.…”

Section: Discussionmentioning

confidence: 99%

Folate-Targeted Gadolinium-Lipid-Based Nanoparticles as a Bimodal Contrast Agent for Tumor Fluorescent and Magnetic Resonance Imaging

Nakamura

Kawano

Shiraishi

et al. 2014

Biological & Pharmaceutical Bulletin

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To enhance tumor magnetic resonance imaging (MRI) signals via the selective accumulation of contrast agents, we prepared folate-modified gadolinium-lipid-based nanoparticles as MRI contrast agents. Folatemodified nanoparticles were comprised of polyethylene glycol (PEG)-lipid, gadolinium diethylenetriamine pentaacetic acid lipid, cationic cholesterol derivatives, folate-conjugated PEG-lipid, and Cy7-PEG-lipid. Folate receptor-mediated cellular nanoparticle association was examined in KB cells, which overexpress the folate receptor. The biodistribution of nanoparticles after their intravenous injection into KB tumor-bearing mice was measured. Mice were imaged through in vivo fluorescence imaging and MRI 24 h after nanoparticle injection, and the intensity enhancement of the tumor MRI signal was evaluated. Increased cellular association of folate-modified nanoparticles was inhibited by excess free folic acid, indicating that nanoparticle association was folate receptor-mediated. Irrespective of folate modification, the amount of nanoparticles in blood 24 h after injection was ca. 10% of the injected dose. Compared with non-modified nanoparticles, folate-modified nanoparticles exhibited significant accumulation in tumor tissues without altering other biodistribution, as well as enhanced tumor fluorescence and MRI signal intensity. The results support the feasibility of MRI-and in vivo fluorescence imaging-based tumor visualization using folate-modified nanoparticles and provide opportunities to develop folate targeting-based imaging applications.Key words folate modification; tumor imaging; lipid-based nanoparticle; magnetic resonance imaging (MRI) contrast agent; KB tumor Magnetic resonance imaging (MRI) is a non-invasive method for tumor detection that provides high-resolution images of anatomical structures. The use of gadolinium (Gd)-based MRI contrast agents shortens the longitudinal relaxation times (T 1 ) of water proton, resulting in signal enhancement of T 1 -weighted images, and improves the detection of the morphological and functional abnormalities of tumors. The usefulness of small molecular contrast agents in clinical practice is limited by low specificity for the intended target tissues, and need to use high concentrations, for signal enhancement. To overcome these shortcomings, a wide variety of macromolecules and nanoparticulate systems have been developed as Gd-based MRI contrast agents, including proteins, 1) dendrimers, 2) polymers, [3][4][5] liposomes, [6][7][8] and micelles. 9-11) Since nano-sized carrier systems passively extravasate from the circulation through the vascular gaps of the tumor neovasculature, a process termed the enhanced permeability and retention (EPR) effect, 12) they have been utilized for the delivery of contrast agents and therapeutic agents to tumors. 11,13) To increase tumor selectivity, these imaging systems were modified with ligands that specifically interact with tumor tissues. [14][15][16][17] The folate receptor is a promising target for tumorspecific contrast ag...

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Noninvasive Visualization of Pharmacokinetics, Biodistribution and Tumor Targeting of Poly[N-(2-hydroxypropyl)methacrylamide] in Mice Using Contrast Enhanced MRI

Abstract: Contrast enhanced MRI is an effective method for non-invasive visualization of in vivo properties of the paramagnetically labeled polymer conjugates in preclinical studies.

Cited by 46 publications

References 27 publications

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

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

Polymer platforms for drug delivery and biomedical imaging

Folate-Targeted Gadolinium-Lipid-Based Nanoparticles as a Bimodal Contrast Agent for Tumor Fluorescent and Magnetic Resonance Imaging

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