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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

Release kinetics of DOX from nanoconjugate P/PEG(5%)/GH-DOX(5%) at pH 5.0 (red) and pH 7.4 (green), at 37 °C.
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f3-ijms-13-11681: Release kinetics of DOX from nanoconjugate P/PEG(5%)/GH-DOX(5%) at pH 5.0 (red) and pH 7.4 (green), at 37 °C.

Mentions: Release of DOX from nanoconjugate P/PEG(5%)/GH-DOX(5%) was measured in order to verify efficient release at pH 5.0 in mature endosome/lysosome and ideally absence of release at physiological pH 7.4 during systemic delivery. The results in Figure 3 show that nanoconjugate exhibited a steady release pattern with a tiny amount of initial burst release and a sustained release thereafter. The release at pH 5.0 was very efficient following a 50% release after 3 h and >80% after 40 h. At physiological pH 7.4, an amount of 10% of the loaded DOX was released after 40 h. This kind of release from nanoparticles is not entirely new and has been observed in many studies before [31–33]. The burst release indicated a possibility of electrostatic binding of positively charged DOX to negatively charged pendant carboxylates of PMLA platform. This amount varied with the degree of purification, but could not be suppressed completely. In contrast, the rapid release at pH 5.0 was accounted for by the acid cleavage of the hydrazone spacer that linked DOX to the nanoconjugate backbone.


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)

Release kinetics of DOX from nanoconjugate P/PEG(5%)/GH-DOX(5%) at pH 5.0 (red) and pH 7.4 (green), at 37 °C.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3-ijms-13-11681: Release kinetics of DOX from nanoconjugate P/PEG(5%)/GH-DOX(5%) at pH 5.0 (red) and pH 7.4 (green), at 37 °C.
Mentions: Release of DOX from nanoconjugate P/PEG(5%)/GH-DOX(5%) was measured in order to verify efficient release at pH 5.0 in mature endosome/lysosome and ideally absence of release at physiological pH 7.4 during systemic delivery. The results in Figure 3 show that nanoconjugate exhibited a steady release pattern with a tiny amount of initial burst release and a sustained release thereafter. The release at pH 5.0 was very efficient following a 50% release after 3 h and >80% after 40 h. At physiological pH 7.4, an amount of 10% of the loaded DOX was released after 40 h. This kind of release from nanoparticles is not entirely new and has been observed in many studies before [31–33]. The burst release indicated a possibility of electrostatic binding of positively charged DOX to negatively charged pendant carboxylates of PMLA platform. This amount varied with the degree of purification, but could not be suppressed completely. In contrast, the rapid release at pH 5.0 was accounted for by the acid cleavage of the hydrazone spacer that linked DOX to the nanoconjugate backbone.

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