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Reformulating Tylocrebrine in Epidermal Growth Factor Receptor Targeted Polymeric Nanoparticles Improves Its Therapeutic Index.

Kirtane AR, Wong HL, Guru BR, Lis LG, Georg GI, Gurvich VJ, Panyam J - Mol. Pharm. (2015)

Bottom Line: Through in vitro studies in different cancer cell lines, we found that EGFR targeted nanoparticles were significantly more effective in killing tumor cells than the free drug.In vivo pharmacokinetic studies revealed that encapsulation in nanoparticles resulted in lower brain penetration and enhanced tumor accumulation of the drug.These results suggest that the therapeutic index of drugs that were previously considered unusable could be significantly improved by reformulation.

View Article: PubMed Central - PubMed

Affiliation: †Department of Pharmaceutics, ‡Institute of Therapeutics Discovery and Development, §Department of Medicinal Chemistry, and ⊥Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.

ABSTRACT
Several promising anticancer drug candidates have been sidelined owing to their poor physicochemical properties or unfavorable pharmacokinetics, resulting in high overall cost of drug discovery and development. Use of alternative formulation strategies that alleviate these issues can help advance new molecules to the clinic at a significantly lower cost. Tylocrebrine is a natural product with potent anticancer activity. Its clinical trial was discontinued following the discovery of severe central nervous system toxicities. To improve the safety and potency of tylocrebrine, we formulated the drug in polymeric nanoparticles targeted to the epidermal growth factor receptor (EGFR) overexpressed on several types of tumors. Through in vitro studies in different cancer cell lines, we found that EGFR targeted nanoparticles were significantly more effective in killing tumor cells than the free drug. In vivo pharmacokinetic studies revealed that encapsulation in nanoparticles resulted in lower brain penetration and enhanced tumor accumulation of the drug. Further, targeted nanoparticles were characterized by significantly enhanced tumor growth inhibitory activity in a mouse xenograft model of epidermoid cancer. These results suggest that the therapeutic index of drugs that were previously considered unusable could be significantly improved by reformulation. Application of novel formulation strategies to previously abandoned drugs provides an opportunity to advance new molecules to the clinic at a lower cost. This can significantly increase the repertoire of treatment options available to cancer patients.

No MeSH data available.


Related in: MedlinePlus

In vitro cytotoxicity of tylocrebrine.A431 andA549 cells were treated with different formulations of tylocrebrineat physiological and acidic extracellular pH. Cell viability was measuredusing MTS assay and normalized to untreated controls. Data representedas mean ± SD, n = 4.
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fig6: In vitro cytotoxicity of tylocrebrine.A431 andA549 cells were treated with different formulations of tylocrebrineat physiological and acidic extracellular pH. Cell viability was measuredusing MTS assay and normalized to untreated controls. Data representedas mean ± SD, n = 4.

Mentions: We compared the in vitro efficacyof various formulations of tylocrebrine in both A549 and A431 cells.Since our previous results showed that acidic pH led to a decreasedintracellular accumulation of tylocrebrine, we performed these studiesunder both physiologic as well as acidic pH conditions. The free drugwas found to be potent in both cell lines under neutral conditions,with IC50 values of 210 and 37 nM (Figure 6A,C). However, there was a dramatic decrease in the efficacy of tylocrebrineunder acidic conditions (compare Figure 6A,Band 6C,D). The IC50 values of tylocrebrineincreased from 210 nM and 37 nM to 432 nM and 361 nM, respectively.At physiological pH, the efficacy of nontargeted tylocrebrine nanoparticleswas comparable to that of the free drug, while targeted tylocrebrinenanoparticles were more effective than the free drug. With a decreasein extracellular pH, the IC50 value of nanoparticle formulations remainedunchanged in A431 cells, while there was a small increase in IC50for the nanoparticle formulations in A549 cells. As a result, bothnontargeted and targeted tylocrebrine nanoparticles showed superiorefficacy than the free drug under acidic conditions. The IC50 valuesestimated from the efficacy studies are summarized in Table 2.


Reformulating Tylocrebrine in Epidermal Growth Factor Receptor Targeted Polymeric Nanoparticles Improves Its Therapeutic Index.

Kirtane AR, Wong HL, Guru BR, Lis LG, Georg GI, Gurvich VJ, Panyam J - Mol. Pharm. (2015)

In vitro cytotoxicity of tylocrebrine.A431 andA549 cells were treated with different formulations of tylocrebrineat physiological and acidic extracellular pH. Cell viability was measuredusing MTS assay and normalized to untreated controls. Data representedas mean ± SD, n = 4.
© Copyright Policy - editor-choice
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4525301&req=5

fig6: In vitro cytotoxicity of tylocrebrine.A431 andA549 cells were treated with different formulations of tylocrebrineat physiological and acidic extracellular pH. Cell viability was measuredusing MTS assay and normalized to untreated controls. Data representedas mean ± SD, n = 4.
Mentions: We compared the in vitro efficacyof various formulations of tylocrebrine in both A549 and A431 cells.Since our previous results showed that acidic pH led to a decreasedintracellular accumulation of tylocrebrine, we performed these studiesunder both physiologic as well as acidic pH conditions. The free drugwas found to be potent in both cell lines under neutral conditions,with IC50 values of 210 and 37 nM (Figure 6A,C). However, there was a dramatic decrease in the efficacy of tylocrebrineunder acidic conditions (compare Figure 6A,Band 6C,D). The IC50 values of tylocrebrineincreased from 210 nM and 37 nM to 432 nM and 361 nM, respectively.At physiological pH, the efficacy of nontargeted tylocrebrine nanoparticleswas comparable to that of the free drug, while targeted tylocrebrinenanoparticles were more effective than the free drug. With a decreasein extracellular pH, the IC50 value of nanoparticle formulations remainedunchanged in A431 cells, while there was a small increase in IC50for the nanoparticle formulations in A549 cells. As a result, bothnontargeted and targeted tylocrebrine nanoparticles showed superiorefficacy than the free drug under acidic conditions. The IC50 valuesestimated from the efficacy studies are summarized in Table 2.

Bottom Line: Through in vitro studies in different cancer cell lines, we found that EGFR targeted nanoparticles were significantly more effective in killing tumor cells than the free drug.In vivo pharmacokinetic studies revealed that encapsulation in nanoparticles resulted in lower brain penetration and enhanced tumor accumulation of the drug.These results suggest that the therapeutic index of drugs that were previously considered unusable could be significantly improved by reformulation.

View Article: PubMed Central - PubMed

Affiliation: †Department of Pharmaceutics, ‡Institute of Therapeutics Discovery and Development, §Department of Medicinal Chemistry, and ⊥Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.

ABSTRACT
Several promising anticancer drug candidates have been sidelined owing to their poor physicochemical properties or unfavorable pharmacokinetics, resulting in high overall cost of drug discovery and development. Use of alternative formulation strategies that alleviate these issues can help advance new molecules to the clinic at a significantly lower cost. Tylocrebrine is a natural product with potent anticancer activity. Its clinical trial was discontinued following the discovery of severe central nervous system toxicities. To improve the safety and potency of tylocrebrine, we formulated the drug in polymeric nanoparticles targeted to the epidermal growth factor receptor (EGFR) overexpressed on several types of tumors. Through in vitro studies in different cancer cell lines, we found that EGFR targeted nanoparticles were significantly more effective in killing tumor cells than the free drug. In vivo pharmacokinetic studies revealed that encapsulation in nanoparticles resulted in lower brain penetration and enhanced tumor accumulation of the drug. Further, targeted nanoparticles were characterized by significantly enhanced tumor growth inhibitory activity in a mouse xenograft model of epidermoid cancer. These results suggest that the therapeutic index of drugs that were previously considered unusable could be significantly improved by reformulation. Application of novel formulation strategies to previously abandoned drugs provides an opportunity to advance new molecules to the clinic at a lower cost. This can significantly increase the repertoire of treatment options available to cancer patients.

No MeSH data available.


Related in: MedlinePlus