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Dual-Modal Tumor Imaging via Long-Circulating Biodegradable Core-Crosslinked Polymeric Micelles.

ABSTRACT: We present a long-circulating biodegradable core-crosslinked polymeric micelle (d-CCPM) for the nuclear/optical imaging of tumors. The d-CCPM was derived from an amphiphilic block-copolymer consisting of a hydrophilic block of brush-like poly(ethylene glycol) and a hydrophobic block containing cleavable pendent triethoxysilane. The resultant imaging tracer had prolonged circulation in the blood (half-life of clearance phase = 36.5 hrs), substantial accumulation in tumor (% injected dose per gram of tissue = 8.5% ± 1.0% at 24 hrs post-injection) and minimal uptake in the liver (5.0% ± 0.1%) or spleen (5.1% ± 0.3%). Both nuclear and near-infrared fluorescence imaging revealed strong signals in tumor regions. At 48 hrs, nuclear imaging exhibited tumor-to-liver and tumor-to-blood ratios of 1.4 and 1.1, respectively. The degradation of d-CCPM was studied in vitro at pH 5.0 and 37°C; and confirmed by transmission electron microscopy confirmed. Our study indicates that the d-CCPM system is an effective probe for dual-modal cancer imaging and a potential safe platform nanocarrier for the delivery of anti-cancer drugs and cancer therapy.

SUBMITTER: Zhao J

PROVIDER: S-EPMC3367665 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Dual-Modal Tumor Imaging via Long-Circulating Biodegradable Core-Crosslinked Polymeric Micelles.

Zhao Jun J Song Shaoli S Zhong Meng M Li Chun C

ACS macro letters 20111211 1

We present a long-circulating biodegradable core-crosslinked polymeric micelle (d-CCPM) for the nuclear/optical imaging of tumors. The d-CCPM was derived from an amphiphilic block-copolymer consisting of a hydrophilic block of brush-like poly(ethylene glycol) and a hydrophobic block containing cleavable pendent triethoxysilane. The resultant imaging tracer had prolonged circulation in the blood (half-life of clearance phase = 36.5 hrs), substantial accumulation in tumor (% injected dose per gram ...[more]

PMID: 22685693

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Project description:The development of novel theranostic nanovectors is of particular interest in treating formidable diseases (e.g., cancers). Herein, we report a new tumor-targetable theranostic agent based on core crosslinked (CCL) micelles, possessing tumor targetable moieties and fluorescence and magnetic resonance (MR) dual imaging modalities. An azide-terminated diblock copolymer, N₃-POEGMA-b-P(DPA-co-GMA), was synthesized via consecutive atom transfer radical polymerization (ATRP), where OEGMA, DPA, and GMA are oligo(ethylene glycol)methyl ether methacrylate, 2-(diisopropylamino)ethyl methacrylate, and glycidyl methacrylate, respectively. The resulting diblock copolymer was further functionalized with DOTA(Gd) (DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakisacetic acid) or benzaldehyde moieties via copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) chemistry, resulting in the formation of DOTA(Gd)-POEGMA-b-P(DPA-co-GMA) and benzaldehyde-POEGMA-b-P(DPA-co-GMA) copolymers. The resultant block copolymers co-assembled into mixed micelles at neutral pH in the presence of tetrakis[4-(2-mercaptoethoxy)phenyl]ethylene (TPE-4SH), which underwent spontaneous crosslinking reactions with GMA residues embedded within the micellar cores, simultaneously switching on TPE fluorescence due to the restriction of intramolecular rotation. Moreover, camptothecin (CPT) was encapsulated into the crosslinked cores at neutral pH, and tumor-targeting pH low insertion peptide (pHLIP, sequence: AEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTCG) moieties were attached to the coronas through the Schiff base chemistry, yielding a theranostic nanovector with fluorescence and MR dual imaging modalities and tumor-targeting capability. The nanovectors can be efficiently taken up by A549 cells, as monitored by TPE fluorescence. After internalization, intracellular acidic pH triggered the release of loaded CPT, killing cancer cells in a selective manner. On the other hand, the nanovectors labeled with DOTA(Gd) contrast agents exhibited increased relaxivity (r₁ = 16.97 mM-1·s-1) compared to alkynyl-DOTA(Gd) small molecule precursor (r₁ = 3.16 mM-1·s-1). Moreover, in vivo MRI (magnetic resonance imaging) measurements revealed CCL micelles with pHLIP peptides exhibiting better tumor accumulation and MR imaging performance as well.

Dataset Information

Dual-Modal Tumor Imaging via Long-Circulating Biodegradable Core-Crosslinked Polymeric Micelles.

Publications

Dual-Modal Tumor Imaging via Long-Circulating Biodegradable Core-Crosslinked Polymeric Micelles.

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