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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

SEC-HPLC chromatograph of nanoconjugate P/PEG(5%)/GH-DOX(5%) after purification using size exclusion chromatography. Eluents were scanned at different wavelengths: (A) 220 nm (near the absorbance maximum for PMLA); (B) 480 nm (absorbance maximum for DOX); (C) 570 nm (DOX fluorescence, excitation at 475 nm) and (D) 220–600 nm wavelength range indicating degree of absorbance by a color code (red > yellow > green > blue > magenta).
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f2-ijms-13-11681: SEC-HPLC chromatograph of nanoconjugate P/PEG(5%)/GH-DOX(5%) after purification using size exclusion chromatography. Eluents were scanned at different wavelengths: (A) 220 nm (near the absorbance maximum for PMLA); (B) 480 nm (absorbance maximum for DOX); (C) 570 nm (DOX fluorescence, excitation at 475 nm) and (D) 220–600 nm wavelength range indicating degree of absorbance by a color code (red > yellow > green > blue > magenta).

Mentions: Nanoconjugate P/PEG(5%)/GH-DOX(5%) was characterized by SEC-HPLC (Figure 2) and polydispersity value P = Mw/Mn = 1.2 (Mw, weight-averaged molecular weight; Mn, number-averaged molecular weight), which was similar to PMLA used in the synthesis, and which is at variance with the different PDI values in Table 1. This finding supports the above assumption of different conformers for the nanoconjugate in dynamic equilibrium that could have affected the high PDI-value by the light scattering technique but escaped detection by SEC-HPLC. Identical retention times at different wavelengths and absence of major other elution peaks suggested high chemical purity. The difference of 0.2 min between positions by absorbance and fluorescence (Figure 2C) corresponded with the time interval between absorbance and fluorescence detections.


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)

SEC-HPLC chromatograph of nanoconjugate P/PEG(5%)/GH-DOX(5%) after purification using size exclusion chromatography. Eluents were scanned at different wavelengths: (A) 220 nm (near the absorbance maximum for PMLA); (B) 480 nm (absorbance maximum for DOX); (C) 570 nm (DOX fluorescence, excitation at 475 nm) and (D) 220–600 nm wavelength range indicating degree of absorbance by a color code (red > yellow > green > blue > magenta).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2-ijms-13-11681: SEC-HPLC chromatograph of nanoconjugate P/PEG(5%)/GH-DOX(5%) after purification using size exclusion chromatography. Eluents were scanned at different wavelengths: (A) 220 nm (near the absorbance maximum for PMLA); (B) 480 nm (absorbance maximum for DOX); (C) 570 nm (DOX fluorescence, excitation at 475 nm) and (D) 220–600 nm wavelength range indicating degree of absorbance by a color code (red > yellow > green > blue > magenta).
Mentions: Nanoconjugate P/PEG(5%)/GH-DOX(5%) was characterized by SEC-HPLC (Figure 2) and polydispersity value P = Mw/Mn = 1.2 (Mw, weight-averaged molecular weight; Mn, number-averaged molecular weight), which was similar to PMLA used in the synthesis, and which is at variance with the different PDI values in Table 1. This finding supports the above assumption of different conformers for the nanoconjugate in dynamic equilibrium that could have affected the high PDI-value by the light scattering technique but escaped detection by SEC-HPLC. Identical retention times at different wavelengths and absence of major other elution peaks suggested high chemical purity. The difference of 0.2 min between positions by absorbance and fluorescence (Figure 2C) corresponded with the time interval between absorbance and fluorescence detections.

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