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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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Schematic presentation of the drug delivery system.
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f1-ijms-13-11681: Schematic presentation of the drug delivery system.

Mentions: We have demonstrated the successful delivery of several anti cancer agents specifically to brain and breast tumor using the targeted nanoconjugate delivery system Polycefin including temozolomide [26] and antisense oligonucleotides [27–29]. This system uses the nanoscale platform poly(β-l-malic acid) (PMLA) known to be biodegradable, non-toxic and non-immunogenic. It provides numerous pendant carboxyl groups accessible for the chemical attachment of drugs and other functional moieties. In order to enlarge our palette for chemotherapeutic drugs, we have chosen here the delivery of DOX. Also, we wished to attach a bactericidal in addition to antisense oligonucleotides and antibodies to be effective during immune compromising anticancer treatments. In this PMLA based delivery vehicle, DOX is bound to the carrier platform via an acid labile hydrazone linker that can be cleaved in the endosomal compartment before delivery to the cytoplasm of the recipient cell. The delivery system is schematically presented in Figure 1. Nanoconjugate contains PEG for protection against resorption by the reticuloendothelial system (RES) and it may optionally contain a fluorescent dye for tracking after systemic injection.


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)

Schematic presentation of the drug delivery system.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1-ijms-13-11681: Schematic presentation of the drug delivery system.
Mentions: We have demonstrated the successful delivery of several anti cancer agents specifically to brain and breast tumor using the targeted nanoconjugate delivery system Polycefin including temozolomide [26] and antisense oligonucleotides [27–29]. This system uses the nanoscale platform poly(β-l-malic acid) (PMLA) known to be biodegradable, non-toxic and non-immunogenic. It provides numerous pendant carboxyl groups accessible for the chemical attachment of drugs and other functional moieties. In order to enlarge our palette for chemotherapeutic drugs, we have chosen here the delivery of DOX. Also, we wished to attach a bactericidal in addition to antisense oligonucleotides and antibodies to be effective during immune compromising anticancer treatments. In this PMLA based delivery vehicle, DOX is bound to the carrier platform via an acid labile hydrazone linker that can be cleaved in the endosomal compartment before delivery to the cytoplasm of the recipient cell. The delivery system is schematically presented in Figure 1. Nanoconjugate contains PEG for protection against resorption by the reticuloendothelial system (RES) and it may optionally contain a fluorescent dye for tracking after systemic injection.

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