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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 vivo tumor inhibition studies.Antitumor efficacyof various formulations of tylocrebrine was determined in mouse A431tumor model. Tumor bearing mice were treated with three doses of tylocrebrine(12 mg/kg) administered at 96 h intervals. Tumor volume was measuredusing a digital caliper. Data represented as mean ± SEM, n = 3–4. ∗ indicates p <0.05 for saline versus targeted nanoparticles and nontargeted nanoparticlesversus targeted nanoparticles.
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fig8: In vivo tumor inhibition studies.Antitumor efficacyof various formulations of tylocrebrine was determined in mouse A431tumor model. Tumor bearing mice were treated with three doses of tylocrebrine(12 mg/kg) administered at 96 h intervals. Tumor volume was measuredusing a digital caliper. Data represented as mean ± SEM, n = 3–4. ∗ indicates p <0.05 for saline versus targeted nanoparticles and nontargeted nanoparticlesversus targeted nanoparticles.

Mentions: We determined the antitumorefficacy of the different formulations of tylocrebrine in A431 tumormodel (Figure 8). There was a reduction intumor growth rate in animals treated with tylocrebrine solution andnontargeted nanoparticles relative to that in the saline-treated animals.Treatment with nontargeted tylocrebrine nanoparticles and tylocrebrinein solution resulted in comparable activities. In agreement with ourpharmacokinetic studies, treatment with EGFR targeted tylocrebrinenanoparticles resulted in greater tumor growth inhibition than thatwith the other formulations.


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 vivo tumor inhibition studies.Antitumor efficacyof various formulations of tylocrebrine was determined in mouse A431tumor model. Tumor bearing mice were treated with three doses of tylocrebrine(12 mg/kg) administered at 96 h intervals. Tumor volume was measuredusing a digital caliper. Data represented as mean ± SEM, n = 3–4. ∗ indicates p <0.05 for saline versus targeted nanoparticles and nontargeted nanoparticlesversus targeted nanoparticles.
© Copyright Policy - editor-choice
Related In: Results  -  Collection

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

fig8: In vivo tumor inhibition studies.Antitumor efficacyof various formulations of tylocrebrine was determined in mouse A431tumor model. Tumor bearing mice were treated with three doses of tylocrebrine(12 mg/kg) administered at 96 h intervals. Tumor volume was measuredusing a digital caliper. Data represented as mean ± SEM, n = 3–4. ∗ indicates p <0.05 for saline versus targeted nanoparticles and nontargeted nanoparticlesversus targeted nanoparticles.
Mentions: We determined the antitumorefficacy of the different formulations of tylocrebrine in A431 tumormodel (Figure 8). There was a reduction intumor growth rate in animals treated with tylocrebrine solution andnontargeted nanoparticles relative to that in the saline-treated animals.Treatment with nontargeted tylocrebrine nanoparticles and tylocrebrinein solution resulted in comparable activities. In agreement with ourpharmacokinetic studies, treatment with EGFR targeted tylocrebrinenanoparticles resulted in greater tumor growth inhibition than thatwith the other formulations.

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