Gene therapy, in principle, can be applicable to the management and cure of a variety of diseases... more Gene therapy, in principle, can be applicable to the management and cure of a variety of diseases, but efficient and targeted delivery of the therapeutic gene to the disease site has been a formidable challenge. Local delivery of genes has some limited utility. But development of a delivery vector that provides tissue and cell targeted gene delivery from systemic administration
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1997
In previous studies we have shown that liposomes sterically stabilized with polyethylene glycol (... more In previous studies we have shown that liposomes sterically stabilized with polyethylene glycol (PEG), preferentially localize in infectious and inflammatory foci. In this study, we further optimized the formulation of PEG liposomes for infection imaging in a rat model. The biodistribution and imaging characteristics of different liposomal formulations labeled with 99mTc were determined in rats with S. aureus infection of the left calf muscle. The influence of liposomal size (mean diameter varying from 90 nm to 220 nm) as well as circulation time (modulated by inclusion of 0-10 mole% phosphatidylserine) were studied. The smallest liposomes displayed improved characteristics for infection imaging: 90-nm liposomes revealed the highest abscess uptake (1.6% +/- 0.4% ID/g, 24 hr postinjection) in combination with the lowest splenic accumulation (6.9% +/- 0.7% ID/g, 24 hr postinjection) as compared to the larger sized preparations. Enhanced abscess-to-blood ratios (4.0 versus 1.3 at 24 hr...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1995
To determine the potential of sterically stabilized liposomes to image infectious and inflammator... more To determine the potential of sterically stabilized liposomes to image infectious and inflammatory foci, the in vivo behavior of 111In-labeled PEGylated (coated with polyethylene glycol) liposomes was studied in a rat model. Indium-111-PEGylated lipsomes were administered intravenously to rats infected with S. aureus in the left calf muscle. The distribution of the radiolabel was studied by gamma counting of dissected tissues and gamma camera imaging for 48 hr. As a reference agent, the preparation of 111In-IgG was included in these studies. Clearance of the PEGylated liposomes from the blood compartment was similar to the clearance of 111In-IgG in this model (t1/2 approximately 20 hr). Uptake of the radiolabel in the abscess with the 111In-liposomes was twice as high as the uptake following injection of 111In-IgG (2.7%ID/g versus 1.1%ID/g at 48 hr postinjection). Tissue counting revealed that abscess-to-muscle ratios reached values up to 20 and 34 (24 and 48 p.i., respectively). As...
The effect of changes in lipid composition on the antitumor activity of doxorubicin (DXR)-contain... more The effect of changes in lipid composition on the antitumor activity of doxorubicin (DXR)-containing liposomes was studied in immunoglobulin solid immunocytoma-bearing Lou/M Wsl rats. Rats bearing a tumor with a diameter between 20 and 30 mm were treated i.v. with 2 mg/kg free DXR or different DXR-containing liposome types for 5 consecutive days followed by one injection more at day 11 after start of therapy. A similar pattern of tumor regression was observed for free DXR and DXR entrapped in "fluid" liposome types. However, DXR entrapped in "solid" liposome types expressed an antitumor activity which was significantly delayed; during the first 3 days after start of therapy solid DXR-containing liposomes were less effective in inducing antitumor activity than fluid DXR-containing liposomes. In order to gain more insight into the mode of action of DXR-containing liposomes, one of the solid liposome types [composed of distearoylphosphatidylcholine, dipalmitoylphosp...
Efficient tumor targeting of polymeric gene transfer systems (polyplexes) represents a major chal... more Efficient tumor targeting of polymeric gene transfer systems (polyplexes) represents a major challenge. To establish tumor targeting after intravenous (IV) administration, the circulation lifetime of these systems should be sufficiently long. Since naked polyplexes are rapidly eliminated from the circulation after IV adminstration, strategies have to be developed to improve their pharmacokinetics. Complexes of plasmid DNA and poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA)-graft-PEG or AB di-block copolymers of pDMAEMA and PEG, as well as PEGylated complexes prepared via PEGylation of preformed complexes (postPEGylation), were evaluated for their physicochemical properties (size and charge) their interactions with blood constituents and transfection activity in vitro. The pharmacokinetics and biodistribution of PEG-polyplexes were studied in mice after IV administration. The degree of accumulation in two subcutaneous (SC) mouse tumors after IV administration was evaluated for the system with the longest circulation time. It is shown that the surface charge of the pDMAEMA-polyplexes was effectively shielded by two PEGylation methods (i.e. the use of pDMAEMA-graft-PEG polymers and postPEGylation). The shielding effect was the highest for the postPEGylation method with PEG(20000), yielding polyplexes that hardly show interactions with blood components (i.e. albumin and erythrocytes) and show substantially prolonged circulation time in mice after IV administration. The superior colloidal stability and circulation kinetics of the postPEGylated polyplexes translated into tumor accumulation which amounted to about 3.5% of the injected dose per gram tumor tissue in a SC Neuro2A tumor model and to about 4.2% of the injected dose per gram tumor tissue in a SC C26 tumor model. This study shows that postPEGylation of pDMAEMA-based polyplexes is the most attractive method to prepare polyplexes with long circulating properties. Tumor targeting capacity after intravenous administration was demonstrated in two subcutaneous tumor models.
The purpose of this study is to evaluate in vivo efficacy and loco-regional distribution of a dox... more The purpose of this study is to evaluate in vivo efficacy and loco-regional distribution of a doxorubicin (DOX)-loaded Polyoxyl 35 Castor Oil (Cremophor EL, CrEL) noncovalent modified single-walled carbon nanotubes (SWNTs) formulation in a sarcoma tumor model after intratumoral injection. The drug loaded SWNTs were successfully prepared via physical absorption, which was confirmed by UV-vis-NIR absorbance spectra and dynamic light scattering assay. Solid tumor models were obtained by injecting mouse sarcoma 180 cells into the thighs of ICR mice. CrEL-SWNTs-DOX, CrEL-SWNTs, free DOX and saline (control) were intratumorally injected after 5 days post transplantation. The biodistribution studies demonstrated that intratumoral delivery of CrEL-SWNTs-DOX resulted in longer drug retention time in tumor, higher tumor level (27.6-fold than that of free DOX), as well as less accumulation in other solid tissues, especially in heart. Furthermore, in vivo anti-tumor activity results showed that CrEL-SWNTs-DOX could effectively suppress the tumor growth than free DOX and the control, attributing to its enhanced intratumoral DOX level. The histopathological findings revealed that the new carbon nanomaterials were a safe vehicle for topical drug delivery systems. It is concluded that this noncovalent modification of carbon nanotubes by CrEL for anticancer agents might be a promising alternative for cancer treatment.
Gene therapy, in principle, can be applicable to the management and cure of a variety of diseases... more Gene therapy, in principle, can be applicable to the management and cure of a variety of diseases, but efficient and targeted delivery of the therapeutic gene to the disease site has been a formidable challenge. Local delivery of genes has some limited utility. But development of a delivery vector that provides tissue and cell targeted gene delivery from systemic administration
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1997
In previous studies we have shown that liposomes sterically stabilized with polyethylene glycol (... more In previous studies we have shown that liposomes sterically stabilized with polyethylene glycol (PEG), preferentially localize in infectious and inflammatory foci. In this study, we further optimized the formulation of PEG liposomes for infection imaging in a rat model. The biodistribution and imaging characteristics of different liposomal formulations labeled with 99mTc were determined in rats with S. aureus infection of the left calf muscle. The influence of liposomal size (mean diameter varying from 90 nm to 220 nm) as well as circulation time (modulated by inclusion of 0-10 mole% phosphatidylserine) were studied. The smallest liposomes displayed improved characteristics for infection imaging: 90-nm liposomes revealed the highest abscess uptake (1.6% +/- 0.4% ID/g, 24 hr postinjection) in combination with the lowest splenic accumulation (6.9% +/- 0.7% ID/g, 24 hr postinjection) as compared to the larger sized preparations. Enhanced abscess-to-blood ratios (4.0 versus 1.3 at 24 hr...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1995
To determine the potential of sterically stabilized liposomes to image infectious and inflammator... more To determine the potential of sterically stabilized liposomes to image infectious and inflammatory foci, the in vivo behavior of 111In-labeled PEGylated (coated with polyethylene glycol) liposomes was studied in a rat model. Indium-111-PEGylated lipsomes were administered intravenously to rats infected with S. aureus in the left calf muscle. The distribution of the radiolabel was studied by gamma counting of dissected tissues and gamma camera imaging for 48 hr. As a reference agent, the preparation of 111In-IgG was included in these studies. Clearance of the PEGylated liposomes from the blood compartment was similar to the clearance of 111In-IgG in this model (t1/2 approximately 20 hr). Uptake of the radiolabel in the abscess with the 111In-liposomes was twice as high as the uptake following injection of 111In-IgG (2.7%ID/g versus 1.1%ID/g at 48 hr postinjection). Tissue counting revealed that abscess-to-muscle ratios reached values up to 20 and 34 (24 and 48 p.i., respectively). As...
The effect of changes in lipid composition on the antitumor activity of doxorubicin (DXR)-contain... more The effect of changes in lipid composition on the antitumor activity of doxorubicin (DXR)-containing liposomes was studied in immunoglobulin solid immunocytoma-bearing Lou/M Wsl rats. Rats bearing a tumor with a diameter between 20 and 30 mm were treated i.v. with 2 mg/kg free DXR or different DXR-containing liposome types for 5 consecutive days followed by one injection more at day 11 after start of therapy. A similar pattern of tumor regression was observed for free DXR and DXR entrapped in "fluid" liposome types. However, DXR entrapped in "solid" liposome types expressed an antitumor activity which was significantly delayed; during the first 3 days after start of therapy solid DXR-containing liposomes were less effective in inducing antitumor activity than fluid DXR-containing liposomes. In order to gain more insight into the mode of action of DXR-containing liposomes, one of the solid liposome types [composed of distearoylphosphatidylcholine, dipalmitoylphosp...
Efficient tumor targeting of polymeric gene transfer systems (polyplexes) represents a major chal... more Efficient tumor targeting of polymeric gene transfer systems (polyplexes) represents a major challenge. To establish tumor targeting after intravenous (IV) administration, the circulation lifetime of these systems should be sufficiently long. Since naked polyplexes are rapidly eliminated from the circulation after IV adminstration, strategies have to be developed to improve their pharmacokinetics. Complexes of plasmid DNA and poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA)-graft-PEG or AB di-block copolymers of pDMAEMA and PEG, as well as PEGylated complexes prepared via PEGylation of preformed complexes (postPEGylation), were evaluated for their physicochemical properties (size and charge) their interactions with blood constituents and transfection activity in vitro. The pharmacokinetics and biodistribution of PEG-polyplexes were studied in mice after IV administration. The degree of accumulation in two subcutaneous (SC) mouse tumors after IV administration was evaluated for the system with the longest circulation time. It is shown that the surface charge of the pDMAEMA-polyplexes was effectively shielded by two PEGylation methods (i.e. the use of pDMAEMA-graft-PEG polymers and postPEGylation). The shielding effect was the highest for the postPEGylation method with PEG(20000), yielding polyplexes that hardly show interactions with blood components (i.e. albumin and erythrocytes) and show substantially prolonged circulation time in mice after IV administration. The superior colloidal stability and circulation kinetics of the postPEGylated polyplexes translated into tumor accumulation which amounted to about 3.5% of the injected dose per gram tumor tissue in a SC Neuro2A tumor model and to about 4.2% of the injected dose per gram tumor tissue in a SC C26 tumor model. This study shows that postPEGylation of pDMAEMA-based polyplexes is the most attractive method to prepare polyplexes with long circulating properties. Tumor targeting capacity after intravenous administration was demonstrated in two subcutaneous tumor models.
The purpose of this study is to evaluate in vivo efficacy and loco-regional distribution of a dox... more The purpose of this study is to evaluate in vivo efficacy and loco-regional distribution of a doxorubicin (DOX)-loaded Polyoxyl 35 Castor Oil (Cremophor EL, CrEL) noncovalent modified single-walled carbon nanotubes (SWNTs) formulation in a sarcoma tumor model after intratumoral injection. The drug loaded SWNTs were successfully prepared via physical absorption, which was confirmed by UV-vis-NIR absorbance spectra and dynamic light scattering assay. Solid tumor models were obtained by injecting mouse sarcoma 180 cells into the thighs of ICR mice. CrEL-SWNTs-DOX, CrEL-SWNTs, free DOX and saline (control) were intratumorally injected after 5 days post transplantation. The biodistribution studies demonstrated that intratumoral delivery of CrEL-SWNTs-DOX resulted in longer drug retention time in tumor, higher tumor level (27.6-fold than that of free DOX), as well as less accumulation in other solid tissues, especially in heart. Furthermore, in vivo anti-tumor activity results showed that CrEL-SWNTs-DOX could effectively suppress the tumor growth than free DOX and the control, attributing to its enhanced intratumoral DOX level. The histopathological findings revealed that the new carbon nanomaterials were a safe vehicle for topical drug delivery systems. It is concluded that this noncovalent modification of carbon nanotubes by CrEL for anticancer agents might be a promising alternative for cancer treatment.
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