Folic Acid and Trastuzumab Functionalized Redox Responsive Polymersomes for Intracellular Doxorubicin Delivery in Breast Cancer.
Redox responsive biodegradable polymersomes comprising of poly(ethylene glycol)-polylactic acid-poly(ethylene glycol) [PEG-s-s-PLA-s-s-PLA-s-s-PEG] triblock copolymer with multiple disulfide linkages were developed to improve intracellular delivery and to enhance chemotherapeutic efficacy of doxorubicin in breast cancer with minimal cardiotoxicity. Folic acid and trastuzumab functionalized monodispersed polymersomes of size ∼150 nm were prepared by nanoprecipitation method while achieving enhanced doxorubicin loading of ∼32% in the polymersomes. Multiple redox responsive disulfide linkages were incorporated in the polymer in order to achieve complete disintegration of polymersomes in redox rich environment of cancer cells resulting in enhanced doxorubicin release as observed in in vitro release studies, where ∼90% doxorubicin release was achieved in pH 5.0 in the presence of 10 mM glutathione (GSH) as compared to ∼20% drug release in pH 7.4. Folic acid and trastuzumab mediated active targeting resulted in improved cellular uptake and enhanced apoptosis in in vitro studies in breast cancer cell lines. In vivo studies in Ehrlich ascites tumor bearing Swiss albino mice showed enhanced antitumor efficacy and minimal cardiotoxicity of polymersomes with ∼90% tumor regression as compared to ∼38% tumor regression observed with free doxorubicin. The results highlight therapeutic potential of the polymersomes as doxorubicin delivery nanocarrier in breast cancer therapy with its superior antitumor efficacy and minimal cardiotoxicity.
†Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India.|‡Biomedical Engineering Unit, All India Institute of Medical Sciences, New Delhi 110029, India.
Shantanu V
SV
Lale
†Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India.|‡Biomedical Engineering Unit, All India Institute of Medical Sciences, New Delhi 110029, India.
Arun
A
Kumar
§Division of Molecular Oncology, Institute of Cytology and Preventive Oncology, Noida 201301, India.
Shyam
S
Prasad
§Division of Molecular Oncology, Institute of Cytology and Preventive Oncology, Noida 201301, India.
Alok C
AC
Bharti
†Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India.|‡Biomedical Engineering Unit, All India Institute of Medical Sciences, New Delhi 110029, India.
Veena
V
Koul
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004337:Drug Carriers / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry*; D065546:Drug Liberation; D005260:Female; D005492:Folic Acid / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D010084:Oxidation-Reduction; D011092:Polyethylene Glycols / Q000737:chemistry; D000068878:Trastuzumab / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004337:Drug Carriers; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; D011092:Polyethylene Glycols; D004317:Doxorubicin; D005492:Folic Acid; D000068878:Trastuzumab