Pharmaceutical Research

, 26:2578 | Cite as

Leucine-Aspartic Acid-Valine Sequence as Targeting Ligand and Drug Carrier for Doxorubicin Delivery to Melanoma Cells: In Vitro Cellular Uptake and Cytotoxicity Studies

  • Sha Zhong
  • Shiladitya Bhattacharya
  • William Chan
  • Bhaskara Jasti
  • Xiaoling Li
Research Paper



To study the feasibility of Leucine-Aspartic Acid-Valine (LDV) as targeting ligand and drug carrier for targeted delivery to integrin α4β1 over-expressing cancer cells.


Poly(L,D,V) was randomly copolymerized using N-carboxyanhydrides of leucine, β-benzyl-aspartic acid, and valine. Oligo(LDV), consisting of 2-6 LDV units, were synthesized by solid phase protein synthesis (SPPS) method. Binding of Leu-Asp-Val, Val-Asp-Leu, and Leu-Asn-Val, and internalization of FITC labeled LDV by wild-type and integrin α4 knock-down A375 cells were studied. Cytotoxicity of poly(L,D,V)-Dox, oligo(LDV)-Dox, and doxorubicin (Dox) was also determined on wild-type, integrin α4 knock-down A375 cells, and normal human epithelial keratinocytes (NHEK).


LDV was essential for the specific binding and internalization by cells expressing integrin α4β1. Cytotoxicity of poly(L,D,V)-Dox and oligo(LDV)-Dox was integrin α4-dependent, while free Dox did not show this differential effect. No observable cytotoxicity trend was found when increasing LDV repeating unit. Poly(L,D,V) was relatively more effective than oligo(LDV) for the delivery of Dox to A375.


LDV containing moieties bind specifically to integrin α4β1 expressing cancer cells. The binding, internalization, and cytotoxicity depend on the level of integrin α4β1 expression. Poly(L,D,V) and oligo(LDV) were both effective in the in vitro targeted delivery of Dox to integrin α4β1 over-expressing A375 cells.


binding specificity cellular uptake LDV oligo(LDV) targeted delivery 



Authors would like to thank Dr. Jianhua Ren and Xiaoning Zhao for providing us with magnetic beads, and Dr. Der Thor for his help on the siRNA knock-down technique. This study is supported by NIH 1R15CA100182-01A2.


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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Sha Zhong
    • 1
  • Shiladitya Bhattacharya
    • 1
  • William Chan
    • 1
  • Bhaskara Jasti
    • 1
  • Xiaoling Li
    • 1
  1. 1.Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy and Health SciencesUniversity of the PacificStocktonUSA

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