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Predicting in vivo efficacy of potential restenosis therapies by cell culture studies: species-dependent susceptibility of vascular smooth muscle cells.

Epstein H, Rabinovich L, Banai S, Elazar V, Gao J, Chorny M, Danenebrg HD, Golomb G - Open Cardiovasc Med J (2008)

Bottom Line: Elucidation of different species sensitivity (rat, rabbit, porcine and human) to diverse drugs (tyrphostins, heparin and bisphsophonates) and a delivery system (nanoparticles) could provide a valuable screening tool for further in vivo studies.The anticipated sensitivity ranking from the explant outgrowth model and SMC mitotic rates (porcine>rat>rabbit>human) do not correlate with the observed relative sensitivity of those animals to antiproliferative therapy in restenosis models (rat>/=rabbit>porcine>human).Similarly, the inhibitory profile of the various antirestenotic drugs in SMC cultures (rabbit>porcine>rat>human) do not correlate with animal studies, the rabbit- and porcine-derived SMC being highly sensitive.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.

ABSTRACT
Although drug-eluting stents (DES) are successfully utilized for restenosis therapy, the development of local and systemic therapeutic means including nanoparticles (NP) continues. Lack of correlation between in vitro and in vivo studies is one of the major drawbacks in developing new drug delivery systems. The present study was designed to examine the applicability of the arterial explant outgrowth model, and of smooth muscle cells (SMC) cultures for prescreening of possible drugs. Elucidation of different species sensitivity (rat, rabbit, porcine and human) to diverse drugs (tyrphostins, heparin and bisphsophonates) and a delivery system (nanoparticles) could provide a valuable screening tool for further in vivo studies. The anticipated sensitivity ranking from the explant outgrowth model and SMC mitotic rates (porcine>rat>rabbit>human) do not correlate with the observed relative sensitivity of those animals to antiproliferative therapy in restenosis models (rat>/=rabbit>porcine>human). Similarly, the inhibitory profile of the various antirestenotic drugs in SMC cultures (rabbit>porcine>rat>human) do not correlate with animal studies, the rabbit- and porcine-derived SMC being highly sensitive. The validity of in vitro culture studies for the screening of controlled release delivery systems such as nanoparticles is limited. It is suggested that prescreening studies of possible drug candidates for restenosis therapy should include both SMC cell cultures of rat and human, appropriately designed with a suitable serum.

No MeSH data available.


Related in: MedlinePlus

Dose response and inhibitory effect on the proliferation of SMC from various species following treatment with AG-1295 in free form, encapsulated in PLA-NP or spiked formulation (blank NP with free drug). For this experiment cells were plated at 2*104 cells per well in 24-well plates and allowed to grow overnight. Triplicate wells were treated with rising concentrations of AG-1295 (5-50µM). The cells were incubated at 37°C for 48hrs and counted using a Coulter counter. AG-1295 caused a marked reduction of SMC proliferation in all species. Note that no significant differences were observed between the various treatments (free drug, NP, or a spiked formulation), but species sensitivity was different. DMSO in the media served as control in AG-1295 experiments.
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Figure 6: Dose response and inhibitory effect on the proliferation of SMC from various species following treatment with AG-1295 in free form, encapsulated in PLA-NP or spiked formulation (blank NP with free drug). For this experiment cells were plated at 2*104 cells per well in 24-well plates and allowed to grow overnight. Triplicate wells were treated with rising concentrations of AG-1295 (5-50µM). The cells were incubated at 37°C for 48hrs and counted using a Coulter counter. AG-1295 caused a marked reduction of SMC proliferation in all species. Note that no significant differences were observed between the various treatments (free drug, NP, or a spiked formulation), but species sensitivity was different. DMSO in the media served as control in AG-1295 experiments.

Mentions: Treatment of SMC by the tyrphostin, AG-1295, encapsulated in NP resulted in a similar degree of inhibition as the free drug in solution (68%, Fig. 6). Empty NP spiked with the drug exhibited a similar inhibitory effect. Different sensitivity was observed among the various species, rabbit>porcine>rat>human (Fig. 6).


Predicting in vivo efficacy of potential restenosis therapies by cell culture studies: species-dependent susceptibility of vascular smooth muscle cells.

Epstein H, Rabinovich L, Banai S, Elazar V, Gao J, Chorny M, Danenebrg HD, Golomb G - Open Cardiovasc Med J (2008)

Dose response and inhibitory effect on the proliferation of SMC from various species following treatment with AG-1295 in free form, encapsulated in PLA-NP or spiked formulation (blank NP with free drug). For this experiment cells were plated at 2*104 cells per well in 24-well plates and allowed to grow overnight. Triplicate wells were treated with rising concentrations of AG-1295 (5-50µM). The cells were incubated at 37°C for 48hrs and counted using a Coulter counter. AG-1295 caused a marked reduction of SMC proliferation in all species. Note that no significant differences were observed between the various treatments (free drug, NP, or a spiked formulation), but species sensitivity was different. DMSO in the media served as control in AG-1295 experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2570571&req=5

Figure 6: Dose response and inhibitory effect on the proliferation of SMC from various species following treatment with AG-1295 in free form, encapsulated in PLA-NP or spiked formulation (blank NP with free drug). For this experiment cells were plated at 2*104 cells per well in 24-well plates and allowed to grow overnight. Triplicate wells were treated with rising concentrations of AG-1295 (5-50µM). The cells were incubated at 37°C for 48hrs and counted using a Coulter counter. AG-1295 caused a marked reduction of SMC proliferation in all species. Note that no significant differences were observed between the various treatments (free drug, NP, or a spiked formulation), but species sensitivity was different. DMSO in the media served as control in AG-1295 experiments.
Mentions: Treatment of SMC by the tyrphostin, AG-1295, encapsulated in NP resulted in a similar degree of inhibition as the free drug in solution (68%, Fig. 6). Empty NP spiked with the drug exhibited a similar inhibitory effect. Different sensitivity was observed among the various species, rabbit>porcine>rat>human (Fig. 6).

Bottom Line: Elucidation of different species sensitivity (rat, rabbit, porcine and human) to diverse drugs (tyrphostins, heparin and bisphsophonates) and a delivery system (nanoparticles) could provide a valuable screening tool for further in vivo studies.The anticipated sensitivity ranking from the explant outgrowth model and SMC mitotic rates (porcine>rat>rabbit>human) do not correlate with the observed relative sensitivity of those animals to antiproliferative therapy in restenosis models (rat>/=rabbit>porcine>human).Similarly, the inhibitory profile of the various antirestenotic drugs in SMC cultures (rabbit>porcine>rat>human) do not correlate with animal studies, the rabbit- and porcine-derived SMC being highly sensitive.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.

ABSTRACT
Although drug-eluting stents (DES) are successfully utilized for restenosis therapy, the development of local and systemic therapeutic means including nanoparticles (NP) continues. Lack of correlation between in vitro and in vivo studies is one of the major drawbacks in developing new drug delivery systems. The present study was designed to examine the applicability of the arterial explant outgrowth model, and of smooth muscle cells (SMC) cultures for prescreening of possible drugs. Elucidation of different species sensitivity (rat, rabbit, porcine and human) to diverse drugs (tyrphostins, heparin and bisphsophonates) and a delivery system (nanoparticles) could provide a valuable screening tool for further in vivo studies. The anticipated sensitivity ranking from the explant outgrowth model and SMC mitotic rates (porcine>rat>rabbit>human) do not correlate with the observed relative sensitivity of those animals to antiproliferative therapy in restenosis models (rat>/=rabbit>porcine>human). Similarly, the inhibitory profile of the various antirestenotic drugs in SMC cultures (rabbit>porcine>rat>human) do not correlate with animal studies, the rabbit- and porcine-derived SMC being highly sensitive. The validity of in vitro culture studies for the screening of controlled release delivery systems such as nanoparticles is limited. It is suggested that prescreening studies of possible drug candidates for restenosis therapy should include both SMC cell cultures of rat and human, appropriately designed with a suitable serum.

No MeSH data available.


Related in: MedlinePlus