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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

Ki67 stainingin tumor sections. Tumors were excised at the endof the efficacy study and stained for Ki67. Representative micrographsof tumor from animals treated with (A) saline, (B) free drug, (C)nontargeted nanoparticles, and (D) targeted nanoparticles are shown.(E) Quantification of Ki67 staining. Data represented as mean ±SEM, n = 6 sections × 3 images/section. ∗indicates p < 0.05.
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fig9: Ki67 stainingin tumor sections. Tumors were excised at the endof the efficacy study and stained for Ki67. Representative micrographsof tumor from animals treated with (A) saline, (B) free drug, (C)nontargeted nanoparticles, and (D) targeted nanoparticles are shown.(E) Quantification of Ki67 staining. Data represented as mean ±SEM, n = 6 sections × 3 images/section. ∗indicates p < 0.05.

Mentions: Tumor samples were stained for Ki67 and cleaved caspase 3to determinethe proliferative and apoptotic indices, respectively. Representativemicrographs of Ki67 staining are shown in Figure 9. Saline-treated animals had significantly higher Ki67+ cells as compared to the other treatment groups. There wasno significant difference in the staining profile of free drug andnontargeted nanoparticle treated tumors. Tumors treated with targetednanoparticles had the lowest Ki67 staining. An opposite profile wasobserved for cleaved caspase 3 expression (Figure 10). Cleaved caspase 3 staining was lowest in saline-treatedanimals and highest in animals treated with targeted nanoparticles.Taken together, these data suggest that treatment with tylocrebrineinhibited tumor cell proliferation and induced apoptosis, with targetednanoparticles resulting in the greatest decrease in tumor cell viability.


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)

Ki67 stainingin tumor sections. Tumors were excised at the endof the efficacy study and stained for Ki67. Representative micrographsof tumor from animals treated with (A) saline, (B) free drug, (C)nontargeted nanoparticles, and (D) targeted nanoparticles are shown.(E) Quantification of Ki67 staining. Data represented as mean ±SEM, n = 6 sections × 3 images/section. ∗indicates p < 0.05.
© Copyright Policy - editor-choice
Related In: Results  -  Collection

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

fig9: Ki67 stainingin tumor sections. Tumors were excised at the endof the efficacy study and stained for Ki67. Representative micrographsof tumor from animals treated with (A) saline, (B) free drug, (C)nontargeted nanoparticles, and (D) targeted nanoparticles are shown.(E) Quantification of Ki67 staining. Data represented as mean ±SEM, n = 6 sections × 3 images/section. ∗indicates p < 0.05.
Mentions: Tumor samples were stained for Ki67 and cleaved caspase 3to determinethe proliferative and apoptotic indices, respectively. Representativemicrographs of Ki67 staining are shown in Figure 9. Saline-treated animals had significantly higher Ki67+ cells as compared to the other treatment groups. There wasno significant difference in the staining profile of free drug andnontargeted nanoparticle treated tumors. Tumors treated with targetednanoparticles had the lowest Ki67 staining. An opposite profile wasobserved for cleaved caspase 3 expression (Figure 10). Cleaved caspase 3 staining was lowest in saline-treatedanimals and highest in animals treated with targeted nanoparticles.Taken together, these data suggest that treatment with tylocrebrineinhibited tumor cell proliferation and induced apoptosis, with targetednanoparticles resulting in the greatest decrease in tumor cell viability.

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