Polymalic acid nanobioconjugate for simultaneous immunostimulation and inhibition of tumor growth in HER2/neu-positive breast cancer

Abstract

Breast cancer remains the second leading cause of cancer death among women in the United States. The breast cancer prognosis is particularly poor in case of tumors overexpressing the oncoprotein HER2/neu. A new nanobioconjugate of the Polycefin 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 ensuring 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 retaining the biological activity of IL-2. We also showed the uptake of the nanobioconjugate by HER2/neu-positive breast cancer cells and enhanced tumor targeting in vivo. In addition, the nanobioconjugate was capable of eliciting anti-tumor activity in immunocompetent mice bearing D2F2/E2 murine mammary tumors that express human HER2/neu. Both IgG1 and IgG2a levels were significantly increased in animals treated with the PMLA-fusion nanobioconjugate compared to animals treated with the antibody–cytokine fusion protein alone or control animals, indicative of the induction of a humoral (TH2) and cell-mediated (TH1) immune responses. Animal survival in vivo was significantly longer after treatment with leading nanobioconjugate with fusion [anti-HER2/neu IgG3-(IL-2)] antibody, p < 0.05. The combination of these molecules on a single polymeric platform is expected to act through direct elimination of cancer cells, inhibition of tumor angiogenesis, and orchestration of a potent immune response against tumor.

Toxicity and efficacy evaluation of multiple targeted polymalic acid conjugates for triple-negative breast cancer treatment

“…Under conditions of advanced cancer, continuous treatment could be necessary until the tumor regresses [27,52,53]. In clinic, however, in many cases the chemotherapy must be discontinued due to life threatening side effects such as liver, kidney, cardio- or neurotoxicity.…”

Nanomedicine therapeutic approaches to overcome cancer drug resistance

“…The drug also contained antisense oligonucleotides against α4 and β1 chains of vascular tumor protein laminin-411 to block angiogenesis. Treatment of immunocompetent mice bearing murine mammary tumors expressing human HER2/neu resulted in significant increases of IgG1 and IgG2a indicative of a humoral (T H 2) and cell-mediated (T H 1) immune response, as well as decreased tumor growth and longer survival [128]. With the increase of resistance to a number of therapeutics, the use of immunostimulatory drugs may prove to be advantageous in avoiding and overcoming drug resistance in the future.…”

Macromolecular therapeutics

“…In addition, its structure should provide drug attachment/release sites for the incorporation of drugs. Different structures have been used and conjugates based on dextran [61], carboxymethyldextran [62], poly(glutamic acid) [63–65], poly(malic acid) [66,67], polyacetals [68,69], poly(vinyl alcohol) [70,71], PEG [72–74], poly(L-γ-glutamyl-glutamine) [75], and polyHPMA [76–78] have been successfully evaluated.…”