Immunomicelles: Targeted pharmaceutical carriers for poorly soluble drugs

Torchilin, Vladimir P.; Lukyanov, Anatoly N.; Gao, Zhonggao; Papahadjopoulos‐Sternberg, Brigitte

doi:10.1073/pnas.0931428100

Cited by 524 publications

(326 citation statements)

References 38 publications

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“…Antibody solution was prepared in 50mM tris-buffered saline, pH 8.7 and incubated with a 10-fold molar excess of pNP-PEG 3400 -PE for 24 h at 4°C to allow the attachment of the antibody to the activated PEG terminus with the simultaneous hydrolysis of non-reacted pNP groups, thus forming the antibody-micelle solution. Then, the required aliquot of this solution was added to liposomes or micelles prepared as described above and incubated for about an hour to allow for the quantitative incorporation of the modified antibody into the appropriate DDS (29).…”

Section: Preparation Of Immunocarriersmentioning

confidence: 99%

“SMART” Drug Delivery Systems: Double-Targeted pH-Responsive Pharmaceutical Nanocarriers

et al. 2006

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In order to develop targeted pharmaceutical carriers additionally capable of responding certain local stimuli, such as decreased pH values in tumors or infarcts, targeted long-circulating PEGylated liposomes and PEG-phosphatidylethanolamine (PEG-PE)-based micelles have been prepared with several functions. First, they are capable of targeting a specific cell or organ by attaching the monoclonal antimyosin antibody 2G4 to their surface via pNP-PEG-PE moieties. Second, these liposomes and micelles were additionally modified with biotin or TAT peptide (TATp) moieties attached to the surface of the nanocarrier by using biotin-PE or TATp-PE or TATp-short PEG-PE derivatives. PEG-PE used for liposome surface modification or for micelle preparation was made degradable by inserting the pH-sensitive hydrazone bond between PEG and PE (PEG-Hz-PE). Under normal pH values, biotin and TATp functions on the surface of nanocarriers were "shielded" by long protecting PEG chains (pH-degradable PEG 2000 -PE or PEG 5000 -PE) or by even longer pNP-PEG-PE moieties used to attach antibodies to the nanocarrier (non-pH-degradable PEG 3400 -PE or PEG 5000 -PE). At pH 7.5-8.0, both liposomes and micelles demonstrated high specific binding with 2G4 antibody substrate, myosin, but very limited binding on an avidin column (biotin-containing nanocarriers) or internalization by NIH/3T3 or U-87 cells (TATp-containing nanocarriers). However, upon brief incubation (15-to-30 min) at lower pH values (pH 5.0-6.0) nanocarriers lost their protective PEG shell because of acidic hydrolysis of PEG-Hz-PE and acquired the ability to become strongly retained on avidin-column (biotin-containing nanocarriers) or effectively internalized by cells via TATp moieties (TATp-containing nanocarriers). We consider this result as the first step in the development of multifunctional stimuli-sensitive pharmaceutical nanocarriers.

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Section: Preparation Of Immunocarriersmentioning

confidence: 99%

“SMART” Drug Delivery Systems: Double-Targeted pH-Responsive Pharmaceutical Nanocarriers

et al. 2006

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“…Please see supporting information (SI) Text for a complete description. The biotinylated monoclonal rat anti-mouse antibody to murine MSR-A types I and II (anti-CD204, monoclonal IgG, Serotec, Raleigh, NC) was used to make immunomicelles by linking the biotinylated micelle with the biotinylated anti-CD204 by a biotin-avidin-biotin bridge using established protocols (18,32). Using established techniques (20), the r 1 of the immunomicelle formulations were determined, in aqueous solution at 60 MHz and 40°C (Bruker Medical, Ettingen, Germany), from a linear fit of Gd concentration (mM Gd) vs. 1/T 1 (1/T 1 ϭ r 1 , s Ϫ1 ).…”

Section: Methodsmentioning

confidence: 99%

Detecting and assessing macrophages in vivo to evaluate atherosclerosis noninvasively using molecular MRI

Amirbekian

Lipinski

Briley‐Saebo

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

340

278

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We investigated the ability of targeted immunomicelles to detect and assess macrophages in atherosclerotic plaque using MRI in vivo. There is a large clinical need for a noninvasive tool to assess atherosclerosis from a molecular and cellular standpoint. Macrophages play a central role in atherosclerosis and are associated with plaques vulnerable to rupture. Therefore, macrophage scavenger receptor (MSR) was chosen as a target for molecular MRI. MSR-targeted immunomicelles, micelles, and gadolinium-diethyltriaminepentaacetic acid (DTPA) were tested in ApoE؊/؊ and WT mice by using in vivo MRI. Confocal laser-scanning microscopy colocalization, macrophage immunostaining and MRI correlation, competitive inhibition, and various other analyses were performed. In vivo MRI revealed that at 24 h postinjection, immunomicelles provided a 79% increase in signal intensity of atherosclerotic aortas in ApoE؊/؊ mice compared with only 34% using untargeted micelles and no enhancement using gadolinium-DTPA. Confocal laser-scanning microscopy revealed colocalization between fluorescent immunomicelles and macrophages in plaques. There was a strong correlation between macrophage content in atherosclerotic plaques and the matched in vivo MRI results as measured by the percent normalized enhancement ratio. Monoclonal antibodies to MSR were able to significantly hinder immunomicelles from providing contrast enhancement of atherosclerotic vessels in vivo. Immunomicelles provided excellent validated in vivo enhancement of atherosclerotic plaques. The enhancement seen is related to the macrophage content of the atherosclerotic vessel areas imaged. Immunomicelles may aid in the detection of high macrophage content associated with plaques vulnerable to rupture. macrophage scavenger receptor ͉ molecular imaging ͉ vulnerable plaque ͉ immunomicelles ͉ gadolinium

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“…In tumor treatment the micelles system has proven effective in regression of tumor size while minimizing damage to the healthy tissues [4] and is being actively investigated in conjunction with hyperthermia [5], ultrasound [6], specific enzyme-induced cleavable bonds [7][8][9], and specific ligands or antibodies [10][11][12][13] for active targeting purposes.…”

Section: Introductionmentioning

confidence: 99%

Tumor pH-responsive flower-like micelles of poly(l-lactic acid)-b-poly(ethylene glycol)-b-poly(l-histidine)

Lee

Kim

et al. 2007

Journal of Controlled Release

420

267

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Polymeric micelles were constructed from poly(L-lactic acid) (PLA; M n 3K)-b-poly(ethylene glycol) (PEG; M n 2K)-b-poly(L-histidine) (polyHis; M n 5K) as a tumor pH-specific anticancer drug carrier. Micelles (particle diameter: ~ 80 nm; critical micelle concentration (CMC): 2 µg/ml) formed by dialysis of the polymer solution in dimethylsulfoxide (DMSO) against pH 8.0 aqueous solution, are assumed to have a flower-like assembly of PLA and polyHis blocks in the core and PEG block as the shell. The pH-sensitivity of the micelles originates from the deformation of the micellar core due to the ionization of polyHis at a slightly acidic pH. However, the co-presence of pH-insensitive lipophilic PLA block in the core prevented disintegration of the micelles and caused swelling/ aggregation. A fluorescence probe study showed that the polarity of pyrene retained in the micelles increased as pH was decreased from 7.4 to 6.6, indicating a change to a more hydrophilic environment in the micelles. Considering that the size increased up to 580 nm at pH 6.6 from 80 nm at pH 7.4 and that the transmittance of micellar solution increased with decreasing pH, the micelles were not dissociated but rather swollen/aggregated. Interestingly, the subsequent decline of pyrene polarity below pH 6.6 suggested re-self-assembly of the block copolymers, most likely forming a PLA block core while polyHis block relocation to the surface. Consequently, these pH-dependent physical changes of the PLA-b-PEG-b-polyHis micelles provide a mechanism for triggered drug release from the micelles triggered by the small change in pH (pH 7.2-6.5).

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Immunomicelles: Targeted pharmaceutical carriers for poorly soluble drugs

Cited by 524 publications

References 38 publications

“SMART” Drug Delivery Systems: Double-Targeted pH-Responsive Pharmaceutical Nanocarriers

“SMART” Drug Delivery Systems: Double-Targeted pH-Responsive Pharmaceutical Nanocarriers

Detecting and assessing macrophages in vivo to evaluate atherosclerosis noninvasively using molecular MRI

Tumor pH-responsive flower-like micelles of poly(l-lactic acid)-b-poly(ethylene glycol)-b-poly(l-histidine)

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