Sequential release of drugs from hollow manganese ferrite nanocarriers for breast cancer therapy

B. N. Prashanth Kumar; Nagaprasad Puvvada; Shashi Rajput; Siddik Sarkar; Swadesh K. Das; Luni Emdad; Devanand Sarkar; P. Venkatesan; Ipsita Pal; Goutam Dey; Suraj Konar; Keith R. Brunt; Raj R. Rao; Abhijit Mazumdar; Subhas C. Kundu; Amita Pathak; Paul B. Fisher; Mahitosh Mandal

doi:10.1039/C4TB01098A

Sequential release of drugs from hollow manganese ferrite nanocarriers for breast cancer therapy†

B. N. Prashanth Kumar,^a Nagaprasad Puvvada,^bd Shashi Rajput,^a Siddik Sarkar,^c Swadesh K. Das,^c Luni Emdad,^c Devanand Sarkar,^c P. Venkatesan,^a Ipsita Pal,^a Goutam Dey,^a Suraj Konar,^b Keith R. Brunt,^d Raj R. Rao,^e Abhijit Mazumdar,^f Subhas C. Kundu,*^g Amita Pathak,*^b Paul B. Fisher^c and Mahitosh Mandal*^a

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^a School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal – 721302, India
E-mail: mahitosh@smst.iitkgp.ernet.in
Fax: +91-3222-282221
Tel: +91-3222-283578

^b Department of Chemistry, Indian Institute of Technology, Kharagpur, West Bengal – 721302, India
E-mail: ami@chem.iitkgp.ernet.in
Fax: +91-3222-255303
Tel: +91-3222-283312

^c Department of Human and Molecular Genetics, VCU Institute of Molecular Genetics, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA23298, USA

^d Department of Pharmacology, Dalhousie Medicine New Brunswick, Dalhousie University, New Brunswick, Canada

^e Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA, USA

^f Department of Clinical Cancer Prevention and Systems Biology, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA

^g Department of Biotechnology, Indian Institute of Technology, Kharagpur, West Bengal – 721302, India
E-mail: kundu@hijli.iitkgp.ernet.in
Fax: +91-3222-278433
Tel: +91-3222-283764

Abstract

Single drug therapies for cancer are often suboptimal and may not provide long term clinical benefits. To overcome this obstacle for effective treatment the applications of two or more drugs are preferable. A limitation of multidrug use is the varying pharmacokinetics of different drugs. To overcome these impediments, we designed and synthesized multi-layered polyvinyl alcohol tethered hollow manganese ferrite nanocarriers capable of encapsulating two drugs with unique attributes of sensitivity towards tumor acidic milieu, mono-dispersive, compactness and high encapsulation efficiency. We encapsulated tamoxifen and diosgenin in the peripheral and subsequent inner layers of multilayered nanocarriers. In vitro and in vivo studies evaluated the nanocarrier uptake and retention ability of the tumor through magnetic saturation studies and elucidated the molecular mechanisms mediating drug(s)-induced apoptosis. The acidity of the tumor environment triggers extracellular dissociation of the peripheral coats resulting in release of tamoxifen blocking the estrogen receptor. The partially degraded nanocarriers localize intracellularly through endosomal escape and release diosgenin. Nanocarrier treatment reduced the cellular levels of Bcl2 and p53, while increasing the levels of Bim. This delivery system successfully embodies the sequential release of drugs and may provide a therapeutic strategy for sequentially affecting multiple targets in advanced cancers.

Journal of Materials Chemistry B

Sequential release of drugs from hollow manganese ferrite nanocarriers for breast cancer therapy†

Abstract

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