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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

1H NMR spectraof PLA–PEG block copolymers. Blockcopolymer of PLA and carboxyl-terminated PEG were synthesized by atwo-step procedure. The starting material (PEG), intermediate product(PLA–PEG-NH2), and final product (PLA–PEG-COOH)were dissolved in deuterated chloroform and analyzed by 1H NMR. Conjugation of lactide to PEG was confirmed by the appearanceof peaks at 1.6 and 5.2 ppm. Conjugation of succinate to the terminalamine group in PEG was confirmed by appearance of a peak at 2.6 ppm.
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fig2: 1H NMR spectraof PLA–PEG block copolymers. Blockcopolymer of PLA and carboxyl-terminated PEG were synthesized by atwo-step procedure. The starting material (PEG), intermediate product(PLA–PEG-NH2), and final product (PLA–PEG-COOH)were dissolved in deuterated chloroform and analyzed by 1H NMR. Conjugation of lactide to PEG was confirmed by the appearanceof peaks at 1.6 and 5.2 ppm. Conjugation of succinate to the terminalamine group in PEG was confirmed by appearance of a peak at 2.6 ppm.

Mentions: PLA–PEG-COOHblock copolymer was used to incorporate carboxyl groups on the surfaceof PLGA nanoparticles. We synthesized PLA–PEG-COOH througha two-step reaction involving the generation of PLA–PEG-NH2 from PEG-NH2 followed by the reaction of the terminalamino group with succinic anhydride. The NMR spectra of PEG-NH2, PLA–PEG-NH2, and PLA–PEG-COOH areshown in Figure 2. Conjugation of lactide toPEG was confirmed by the appearance of peaks at δ = 5.3 ppmand δ = 1.6 ppm.24 Conjugation ofsuccinate moiety to PLA–PEG-NH2 was confirmed bythe appearance of a peak at δ = 2.6 ppm.13 On the basis of the AUC of the peaks, the molecular weightof PLA was estimated to be ∼15 kDa.


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)

1H NMR spectraof PLA–PEG block copolymers. Blockcopolymer of PLA and carboxyl-terminated PEG were synthesized by atwo-step procedure. The starting material (PEG), intermediate product(PLA–PEG-NH2), and final product (PLA–PEG-COOH)were dissolved in deuterated chloroform and analyzed by 1H NMR. Conjugation of lactide to PEG was confirmed by the appearanceof peaks at 1.6 and 5.2 ppm. Conjugation of succinate to the terminalamine group in PEG was confirmed by appearance of a peak at 2.6 ppm.
© Copyright Policy - editor-choice
Related In: Results  -  Collection

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

fig2: 1H NMR spectraof PLA–PEG block copolymers. Blockcopolymer of PLA and carboxyl-terminated PEG were synthesized by atwo-step procedure. The starting material (PEG), intermediate product(PLA–PEG-NH2), and final product (PLA–PEG-COOH)were dissolved in deuterated chloroform and analyzed by 1H NMR. Conjugation of lactide to PEG was confirmed by the appearanceof peaks at 1.6 and 5.2 ppm. Conjugation of succinate to the terminalamine group in PEG was confirmed by appearance of a peak at 2.6 ppm.
Mentions: PLA–PEG-COOHblock copolymer was used to incorporate carboxyl groups on the surfaceof PLGA nanoparticles. We synthesized PLA–PEG-COOH througha two-step reaction involving the generation of PLA–PEG-NH2 from PEG-NH2 followed by the reaction of the terminalamino group with succinic anhydride. The NMR spectra of PEG-NH2, PLA–PEG-NH2, and PLA–PEG-COOH areshown in Figure 2. Conjugation of lactide toPEG was confirmed by the appearance of peaks at δ = 5.3 ppmand δ = 1.6 ppm.24 Conjugation ofsuccinate moiety to PLA–PEG-NH2 was confirmed bythe appearance of a peak at δ = 2.6 ppm.13 On the basis of the AUC of the peaks, the molecular weightof PLA was estimated to be ∼15 kDa.

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