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Cellular delivery of doxorubicin via pH-controlled hydrazone linkage using multifunctional nano vehicle based on poly(β-l-malic acid).

Patil R, Portilla-Arias J, Ding H, Konda B, Rekechenetskiy A, Inoue S, Black KL, Holler E, Ljubimova JY - Int J Mol Sci (2012)

Bottom Line: Doxorubicin (DOX) is currently used in cancer chemotherapy to treat many tumors and shows improved delivery, reduced toxicity and higher treatment efficacy when being part of nanoscale delivery systems.This is why in our work we aimed to improve DOX delivery and reduce the toxicity by chemical conjugation with a new nanoplatform based on polymalic acid.DOX-nanoconjugates were found stable under physiological conditions and shown to successfully inhibit in vitro cancer cell growth of several invasive breast carcinoma cell lines such as MDA-MB-231 and MDA-MB- 468 and of primary glioma cell lines such as U87MG and U251.

View Article: PubMed Central - PubMed

Affiliation: Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 110 N. George Burns Rd. Davis Building, Room 2094-A, Los Angeles, CA 90048, USA; E-Mails: portillaj@cshs.org (J.P.-A.); dinghx@cshs.org (H.D.); kondab@cshs.org (B.K.); rekechenetskiya@cshs.org (A.R.); inoues@cshs.org (S.I.); blackk@cshs.org (K.L.B.); ljubimovaj@cshs.org (J.Y.L.).

ABSTRACT
Doxorubicin (DOX) is currently used in cancer chemotherapy to treat many tumors and shows improved delivery, reduced toxicity and higher treatment efficacy when being part of nanoscale delivery systems. However, a major drawback remains its toxicity to healthy tissue and the development of multi-drug resistance during prolonged treatment. This is why in our work we aimed to improve DOX delivery and reduce the toxicity by chemical conjugation with a new nanoplatform based on polymalic acid. For delivery into recipient cancer cells, DOX was conjugated via pH-sensitive hydrazone linkage along with polyethylene glycol (PEG) to a biodegradable, non-toxic and non-immunogenic nanoconjugate platform: poly(β-l-malic acid) (PMLA). DOX-nanoconjugates were found stable under physiological conditions and shown to successfully inhibit in vitro cancer cell growth of several invasive breast carcinoma cell lines such as MDA-MB-231 and MDA-MB- 468 and of primary glioma cell lines such as U87MG and U251.

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Related in: MedlinePlus

Synthesis of P/PEG(5%)/GH-DOX(5%). Reagents and conditions: (i) Mixture of NHS and DCC, Acetone, DMF, RT 3 h, followed by addition of mPEG5000-NH2, RT 45 min, and by glycine hydrazide, 2 h yield 67%; (ii) DOX.HCl, molecular sieves 4 Å, 10–18 mesh, DMF, RT 16 h, yield 72%.
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f6-ijms-13-11681: Synthesis of P/PEG(5%)/GH-DOX(5%). Reagents and conditions: (i) Mixture of NHS and DCC, Acetone, DMF, RT 3 h, followed by addition of mPEG5000-NH2, RT 45 min, and by glycine hydrazide, 2 h yield 67%; (ii) DOX.HCl, molecular sieves 4 Å, 10–18 mesh, DMF, RT 16 h, yield 72%.

Mentions: The multi-component drug delivery system was synthesized using PMLA as polymer platform. Synthesis of nanoconjugate proceeded very smoothly and involved two major steps. As presented in Scheme II, the first step resulted in the chemical activation of all the PMLA pendant carboxyl groups with DCC/NHS mixture forming the NHS-ester. Subsequent nucleophilic replacement by mPEG-amine and glycine spacer was achieved with ease forming stable amide bonds. These reagents were used in limiting stoichiometries and their reactions were completed as indicated by TLC/ninhydrin tests. On this basis, the percent loading corresponds with the amounts of reagents. Remaining unused activated ester was then hydrolyzed under acidic pH (5.5); during this process the Boc group of glycine spacer was also removed.


Cellular delivery of doxorubicin via pH-controlled hydrazone linkage using multifunctional nano vehicle based on poly(β-l-malic acid).

Patil R, Portilla-Arias J, Ding H, Konda B, Rekechenetskiy A, Inoue S, Black KL, Holler E, Ljubimova JY - Int J Mol Sci (2012)

Synthesis of P/PEG(5%)/GH-DOX(5%). Reagents and conditions: (i) Mixture of NHS and DCC, Acetone, DMF, RT 3 h, followed by addition of mPEG5000-NH2, RT 45 min, and by glycine hydrazide, 2 h yield 67%; (ii) DOX.HCl, molecular sieves 4 Å, 10–18 mesh, DMF, RT 16 h, yield 72%.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472769&req=5

f6-ijms-13-11681: Synthesis of P/PEG(5%)/GH-DOX(5%). Reagents and conditions: (i) Mixture of NHS and DCC, Acetone, DMF, RT 3 h, followed by addition of mPEG5000-NH2, RT 45 min, and by glycine hydrazide, 2 h yield 67%; (ii) DOX.HCl, molecular sieves 4 Å, 10–18 mesh, DMF, RT 16 h, yield 72%.
Mentions: The multi-component drug delivery system was synthesized using PMLA as polymer platform. Synthesis of nanoconjugate proceeded very smoothly and involved two major steps. As presented in Scheme II, the first step resulted in the chemical activation of all the PMLA pendant carboxyl groups with DCC/NHS mixture forming the NHS-ester. Subsequent nucleophilic replacement by mPEG-amine and glycine spacer was achieved with ease forming stable amide bonds. These reagents were used in limiting stoichiometries and their reactions were completed as indicated by TLC/ninhydrin tests. On this basis, the percent loading corresponds with the amounts of reagents. Remaining unused activated ester was then hydrolyzed under acidic pH (5.5); during this process the Boc group of glycine spacer was also removed.

Bottom Line: Doxorubicin (DOX) is currently used in cancer chemotherapy to treat many tumors and shows improved delivery, reduced toxicity and higher treatment efficacy when being part of nanoscale delivery systems.This is why in our work we aimed to improve DOX delivery and reduce the toxicity by chemical conjugation with a new nanoplatform based on polymalic acid.DOX-nanoconjugates were found stable under physiological conditions and shown to successfully inhibit in vitro cancer cell growth of several invasive breast carcinoma cell lines such as MDA-MB-231 and MDA-MB- 468 and of primary glioma cell lines such as U87MG and U251.

View Article: PubMed Central - PubMed

Affiliation: Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, 110 N. George Burns Rd. Davis Building, Room 2094-A, Los Angeles, CA 90048, USA; E-Mails: portillaj@cshs.org (J.P.-A.); dinghx@cshs.org (H.D.); kondab@cshs.org (B.K.); rekechenetskiya@cshs.org (A.R.); inoues@cshs.org (S.I.); blackk@cshs.org (K.L.B.); ljubimovaj@cshs.org (J.Y.L.).

ABSTRACT
Doxorubicin (DOX) is currently used in cancer chemotherapy to treat many tumors and shows improved delivery, reduced toxicity and higher treatment efficacy when being part of nanoscale delivery systems. However, a major drawback remains its toxicity to healthy tissue and the development of multi-drug resistance during prolonged treatment. This is why in our work we aimed to improve DOX delivery and reduce the toxicity by chemical conjugation with a new nanoplatform based on polymalic acid. For delivery into recipient cancer cells, DOX was conjugated via pH-sensitive hydrazone linkage along with polyethylene glycol (PEG) to a biodegradable, non-toxic and non-immunogenic nanoconjugate platform: poly(β-l-malic acid) (PMLA). DOX-nanoconjugates were found stable under physiological conditions and shown to successfully inhibit in vitro cancer cell growth of several invasive breast carcinoma cell lines such as MDA-MB-231 and MDA-MB- 468 and of primary glioma cell lines such as U87MG and U251.

Show MeSH
Related in: MedlinePlus