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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

Effect of conjugationtime on targeting peptide conjugation efficiencyand drug loading. EGFR-targeting peptide was conjugated to the surfaceof nanoparticles using NHS–EDC chemistry. The influence ofreaction time on (A) conjugation efficiency of the peptide and (B)drug loading is shown. Data represented as mean ± SD, n = 3.
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fig3: Effect of conjugationtime on targeting peptide conjugation efficiencyand drug loading. EGFR-targeting peptide was conjugated to the surfaceof nanoparticles using NHS–EDC chemistry. The influence ofreaction time on (A) conjugation efficiency of the peptide and (B)drug loading is shown. Data represented as mean ± SD, n = 3.

Mentions: Weinitially determined the effect of reaction time on drug loading innanoparticles and efficiency of targeting peptide conjugation to thesurface of nanoparticles. Increasing the reaction time resulted inan increase in peptide conjugation efficiency but resulted in decreaseddrug loading (Figure 3). Particle size andzeta potential were unaffected by the duration of the reaction time.In general, the particle size was found to be in the range of 300–400nm, and the particles had a net negative zeta potential (Table 1). We used an intermediate reaction time (5 h) forachieving optimum drug loading and conjugation efficiency. The drugand peptide loading for nanoparticles used in the rest of the studiesare summarized in Table 1.


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)

Effect of conjugationtime on targeting peptide conjugation efficiencyand drug loading. EGFR-targeting peptide was conjugated to the surfaceof nanoparticles using NHS–EDC chemistry. The influence ofreaction time on (A) conjugation efficiency of the peptide and (B)drug loading is shown. Data represented as mean ± SD, n = 3.
© Copyright Policy - editor-choice
Related In: Results  -  Collection

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

fig3: Effect of conjugationtime on targeting peptide conjugation efficiencyand drug loading. EGFR-targeting peptide was conjugated to the surfaceof nanoparticles using NHS–EDC chemistry. The influence ofreaction time on (A) conjugation efficiency of the peptide and (B)drug loading is shown. Data represented as mean ± SD, n = 3.
Mentions: Weinitially determined the effect of reaction time on drug loading innanoparticles and efficiency of targeting peptide conjugation to thesurface of nanoparticles. Increasing the reaction time resulted inan increase in peptide conjugation efficiency but resulted in decreaseddrug loading (Figure 3). Particle size andzeta potential were unaffected by the duration of the reaction time.In general, the particle size was found to be in the range of 300–400nm, and the particles had a net negative zeta potential (Table 1). We used an intermediate reaction time (5 h) forachieving optimum drug loading and conjugation efficiency. The drugand peptide loading for nanoparticles used in the rest of the studiesare summarized in Table 1.

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