IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
artículos
Título:
Polymalic acid nanobioconjugate for simultaneous immunostimulation and inhibition of tumor growth in HER2/neu-positive breast cancer
Autor/es:
DING H.; HELGUERA G.; RODRIGUEZ J. A.; MARKMAN J.; LURIA-PÉREZ R.; GANGALUM P.; PORTILLA-ARIAS J.; INOUE S.; DANIELS-WELLS T.; BLACK K.; HOLLER E.; PENICHET M. L.; LJUBIMOVA J. Y.
Revista:
JOURNAL OF CONTROLLED RELEASE
Editorial:
ELSEVIER SCIENCE BV
Referencias:
Lugar: Amsterdam; Año: 2013 p. 322 - 329
ISSN:
0168-3659
Resumen:
Breast cancer remains the second leading cause of cancer death among
women in the United States. Breast cancer prognosis is particularly poor
in case of tumors overexpressing the oncoprotein HER2/neu. A new
nanobioconjugate of the Polycefin(TM) family of anti-cancer drugs based
on biodegradable and non-toxic polymalic acid (PMLA) was engineered for a
multi-pronged attack on HER2/neu-positive breast cancer cells. An
antibody-cytokine fusion protein consisting of the immunostimulatory
cytokine interleukin-2 (IL-2) genetically fused to an antibody specific
for human HER2/neu [anti-HER2/neu IgG3-(IL-2)] was covalently attached
to the PMLA backbone to target HER2/neu expressing tumors and ensure the
delivery of IL-2 to the tumor microenvironment. Antisense
oligonucleotides (AON) were conjugated to the nanodrug to inhibit the
expression of vascular tumor protein laminin-411 in order to block tumor
angiogenesis. It is shown that the nanobioconjugate was capable of
specifically binding human HER2/neu and retained the biological activity
of IL-2. We also showed the uptake of the nanobioconjugate into
HER2/neu-positive breast cancer cells and enhanced tumor targeting in
vivo. The nanobioconjugate exhibited marked anti-tumor activity
manifested by significantly longer animal survival and significantly
increased anti-HER2/neu immune response in immunocompetent mice bearing
D2F2/E2 murine mammary tumors that express human HER2/neu. The
combination of laminin-411 AON and antibody-cytokine fusion protein on a
single polymeric platform results in a new nanobioconjugate that can
act against cancer cells through inhibition of tumor growth and
angiogenesis and the orchestration of an immune response against the
tumor. The present Polycefin(TM) variant may be a promising agent for
treating HER2/neu expressing tumors and demonstrates the versatility of
the Polycefin(TM) nanobioconjugate platform.