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Updated: Sep 8, 2025
Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Development of a cancer cells self‑activating and miR‑125a‑5p expressing poly‑pharmacological nanodrug for cancer
Yung-Chieh Chang1, Min-Chieh Shieh2, Yen-Hsuan Chang3
1Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan, R.O.C.
Abstract:
Cancer cells can acquire resistance to targeted therapeutic agents when the designated targets or their downstream signaling molecules develop protein conformational or activity changes. There is an increasing interest in developing poly‑pharmacologic anticancer agents to target multiple oncoproteins or signaling pathways in cancer cells. The microRNA 125a‑5p (miR‑125a‑5p) is a tumor suppressor, and its expression has frequently been downregulated in tumors. By contrast, the anti‑apoptotic molecule BIRC5/SURVIVIN is highly expressed in tumors but not in the differentiated normal tissues. In the present study, the development of a BIRC5 gene promoter‑driven, miR‑125a‑5p expressing, poly‑L‑lysine‑conjugated magnetite iron poly‑pharmacologic nanodrug (pL‑MNP‑pSur‑125a) was reported. The cancer cells self‑activating property and the anticancer effects of this nanodrug were examined in both the multidrug efflux protein ABCB1/MDR1‑expressing/‑non‑expressing cancer cells in vitro and in vivo. It was demonstrated that pL‑MNP‑pSur‑125a decreased the expression of ERBB2/HER2, HDAC5, BIRC5, and SP1, which are hot therapeutic targets for cancer in vitro. Notably, pL‑MNP‑pSur‑125a also downregulated the expression of TDO2 in the human KB cervical carcinoma cells. PL‑MNP‑pSur‑125a decreased the viability of various BIRC5‑expressing cancer cells, regardless of the tissue origin or the expression of ABCB1, but not of the human BIRC5‑non‑expressing HMEC‑1 endothelial cells. In vivo, pL‑MNP‑pSur‑125a exhibited potent antitumor growth effects, but without inducing liver toxicity, in various zebrafish human‑ABCB1‑expressing and ABCB1‑non‑expressing tumor xenograft models. In conclusion, pL‑MNP‑pSur‑125a is an easy‑to‑prepare and a promising poly‑pharmacological anticancer nanodrug that has the potential to manage numerous malignancies, particularly for patients with BIRC5/ABCB1‑related drug resistance after prolonged chemotherapeutic treatments.
Insights
A novel nanodrug, pL-MNP-pSur-125a, effectively targets multiple cancer pathways and overcomes drug resistance. This poly-pharmacologic agent shows potent antitumor effects in vitro and in vivo with minimal toxicity, offering a promising strategy for diverse malignancies.
Area of Science:
- Nanomedicine and Drug Delivery
- Oncology and Cancer Therapeutics
- Molecular Biology and Genetics
Background:
- Cancer cells develop therapeutic resistance through target alterations and increased drug efflux.
- Targeting multiple pathways with poly-pharmacologic agents is a growing strategy to overcome resistance.
- MicroRNA 125a-5p (miR-125a-5p) is a tumor suppressor, often downregulated in cancers, while BIRC5/SURVIVIN is an anti-apoptotic protein highly expressed in tumors.
Purpose of the Study:
- To develop and evaluate a novel poly-pharmacologic nanodrug, pL-MNP-pSur-125a, for cancer treatment.
- To assess the self-activating and anticancer properties of the nanodrug in vitro and in vivo.
- To investigate the nanodrug's efficacy in cancer cells with varying expression of multidrug resistance proteins (ABCB1/MDR1).
Main Methods:
- Development of a BIRC5 gene promoter-driven, miR-125a-5p expressing, poly-L-lysine-conjugated magnetite iron nanodrug (pL-MNP-pSur-125a).
- In vitro evaluation of nanodrug effects on cancer cell viability and expression of key targets (ERBB2/HER2, HDAC5, BIRC5, SP1, TDO2) in ABCB1-expressing and non-expressing cells.
- In vivo assessment of antitumor growth effects and liver toxicity in zebrafish tumor xenograft models.
Main Results:
- pL-MNP-pSur-125a decreased the expression of multiple cancer targets including ERBB2/HER2, HDAC5, BIRC5, and SP1 in vitro.
- The nanodrug reduced the viability of BIRC5-expressing cancer cells, irrespective of ABCB1 expression, but not in BIRC5-non-expressing cells.
- In vivo studies demonstrated potent antitumor effects in zebrafish models without inducing liver toxicity.
Conclusions:
- pL-MNP-pSur-125a is a readily prepared, promising poly-pharmacologic nanodrug with broad anticancer potential.
- The nanodrug effectively targets multiple oncogenic pathways and overcomes ABCB1-mediated drug resistance.
- This nanodrug offers a potential therapeutic strategy for managing various malignancies, especially those with BIRC5/ABCB1-related resistance.
