Liposomal Nanomedicine for Breast Cancer Therapy

Table 1. List of different molecular targets present on breast cancer cells and their respective ligands used for targeted drug delivery.
Receptor category	Target receptor	Natural ligand	Synthetic ligand	Ref.
Steroids	Estrogen receptor	Estrogens	Tamoxifen	[8]
	Progesterone receptor	Progesterone	Medroxyprogesterone acetate	[7]
	Androgen receptor	Dihydrotestosterone	Hydroxyflutamide	[127]
	Glucocorticoid receptor	Cortisol	CP-394531, CP-409069	[127]
Nonsteroids	Thyroid receptor	Tri-iodothyronine	None	[19,20]
	Vitamin D receptor	1α,25-(OH)₂D₃	1α-(OH)₂D₅, EB1089	[11,12]
	Retinoic acid receptor	Retinoic acid	All-trans retinoic acid	[16]
	Retinoic-X receptor	Retinoic acid	All-trans retinoic acid, 9-cis retinoic acid	[14,128]
	Peroxisome proliferators-activated receptor	15-deoxy-Δ12,14-prostaglandin	Troglitazone	[24]
	Farnesoid X-activated receptor	Bile acid	SR-45023A	[127]
	Constitutive active receptor	Phenobarbital	None	[127]
Signal transduction modulatorsCell-cycle and apoptosis modulation	Endothelial growth factor receptor	Endothelial growth factors	Gefitinib, Erlotinib	[129]
	HER2/neu	-	Trastuzumab	[130]
	c-kit Ras family	Kit ligand, steel factor	Imatinib mesylate	[31]
	p53	-	CP-31398	[43]
Angiogenesis modulation	VEGF receptor	Growth factors	Bevacizumab, Imatinib	[131]
	PDGF receptor	PDGF	Tanomastat	[132]
	Integrins	-	RGD peptide	[133]
	Matrix metalloproteinases	MMP substrate peptide	anti-MT1-MMP	[134]

Table 2. List of liposome-based formulations for breast cancer therapy available on the market and in different clinical trail phases.
Drug	Name of formulation	Present status	Company
Doxorubicin	Doxil®	Marketed	Centocor Ortho Biotech Products Ltd., USA
Doxorubicin	D-99	Marketed	Elan Pharma, Princeton, NJ, USA
Doxorubicin	Myocet®	Marketed	Elan Pharma, Princeton, NJ, USA
Doxorubicin	Caelyx®	Marketed (Outside USA)	Schering-Plough Corporation, Europe
Paclitaxel	LEP-ETU	Phase I	Neo Pharma, Inc., USA
Paclitaxel	MBT-0206	Phase I	MediGene AG, Munich, Germany
Mitroxatrone	LEM-ETU	Phase I	Neo Pharma, Inc., USA
Docetaxal	ATI-1123	Phase I	Azaya Therapeutics, Inc., San Antonio, TX, USA
Vinorelbine	INX-0125	Phase II	Inex Pharm Co., Vancouver, BC, Canada
Annamycin	Liposomal-Annamycin®	Phase II	MD Anderson CC, Houston, TX, USA
Doxorubicin	ThermoDox®	Phase I/II	Celsion Corporation, New York, NY, USA

Table 3. List of ligands that have been anchored on liposomes for breast cancer targeting.
Target site	Targeting ligand	Ref.
CD44 receptors	HA	[97,98]
Estrogen receptors	Estrogen, tamoxifen	[80,81]
Folate receptors	Folic acid	[76,77]
Her2/neu	Transtuzumab	[72,73]
MT1-MMP	Anti-MT1-MMP	[89]
MUC1	mAb B27.29	[87]
TfR	Transferrin, anti-TfR	[84,85]
VEGF receptor	Bevacizumab, sunitinib	[90,91]
α_vβ₃ integrin	RGD peptides and nonpeptide mimetics	[82,83]

HA: Hyaluronic acid; MT1-MMP: Membrane type-1 matrix metalloproteinase; RGD: Arginine-glycine-aspartic acid; TfR: Transferrin receptor.

Table 4. Summary of reports in the literature related to liposome-based gene therapy of breast cancer.
Gene used	Targeting ligand	Targeting site	Remark	Ref.
p53 tumor suppressor gene	scFv of anti-transferrin receptor	Transferrin receptors	It was reported that scFv-cys targeted the cationic liposome–DNA complex (lipoplex) to tumor cells and subsequently enhanced the transfection efficiencies both in vitro and in vivo in a variety of human breast tumor models	[120]
CMV-SPORT-β-gal	Haloperidol	Sigma receptors	Haloperidol-conjugated targeted lipoplex showed tenfold higher reporter gene expression in MCF-7 cells in comparison to control lipoplex	[123]
p53	Estradiol	Estrogen receptors	Targeting lipoplex can indeed induce cell death, possibly through apoptosis, in a target-specific manner	[124]
β-galactosidase or GFP	C16-A7R	NRP-1	Liposomes were reported to be accumulated in human breast cancer cells MDA-MB-231, which overexpress NRP-1	[135]
Plasmid DNA pCMV-luc	HA	CD44	HA-DOPE after incorporation in to liposomes increased the level of transfection on CD44-expressing MDA-MB-231 cells in comparison to the MCF-7 line, which expresses very low levels of CD44	[136]

GFP: Green fluorescent protein; HA: Hyaluronic acid; NRP: Neuropilin; scFv: Single-chain antibody Fv fragment.

Breast Cancer

Breast cancer is the second leading cause of death among women worldwide.
Chemotherapy of breast cancer is full of numerous side effects associated with uncontrolled biodistribution of cytotoxic agent after systemic administration.

Molecular Targets on Breast Cancer Cells & Drug Targeting

Breast cancer cells overexpress unique markers for their rapid growth and proliferation, which may serve as receptors for targeted chemotherapy.
These molecular targets can be classified in hormonal (i.e., steroid receptors, such as estrogen receptor and progesterone receptor) and nonsteriod receptors (e.g., thyroid, vitamin D and retinoid).
Drug–ligand conjugates and ligand-anchored carrier systems encapsulating drug/gene have been developed and well characterized for the purpose of targeted breast cancer therapy.

Liposomal Nanomedicine for Breast Cancer Therapy

Liposomes serve as a versatile tool in drug-delivery science and technology.
Nanoliposomes loaded with bioactives for controlled and targeted delivery of these agents to their site of action are termed liposomal nanomedicine.
Multifunctional liposomes, which utilize molecular alterations/expressions by tumor cells, remains the thrust area of research in the field of nanomedicine for breast cancer therapy.

Authors and Disclosures