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Posted: Jul 25th, 2012
Multifunctional nanoplatform safely delivers tumor drugs to their target
(Nanowerk Spotlight) A major obstacle in today's chemical cancer therapies is to achieve specific drug accumulation at tumor sites and even tumor cells, because most chemotherapeutic agents are insoluble and instable, and can not differentiate between diseased and healthy cells. This often leads to severe adverse effects on healthy tissues and limits the maximum dose that can safely administered to patients. This issue becomes more serious in the case of some highly effective therapeutic agents, given that most potent anticancer drugs exhibit acute toxicity and narrow therapeutic window, and the clinical utility may not be possible without a powerful delivery systems equipped with smart properties that can allow them to precisely access the target tissues and cells.
Targeted delivery approaches using nanomedicines will be able to provide solutions to these problems.
To realize nanomedicine's potential, nanocarriers must be engineered to demonstrate multiple properties in a smart and coordinated way, such as long circulation, targeting activity, cellular internalization as well as triggered release of drugs within tumor cells.
In spite of persistent efforts in developing multifunctional nanomedicines, the combination of multiple functions in one system still represents a great challenge for scientists. The difficulty and complexity behind fabricating viable multifunctional nanovessels may prevent targeted formulations from being approved by the U.S. Food and Drug Administration (FDA) and other country's equivalent regulatory bodies and make them difficult to be translated into clinical applications.
"For the polymeric nanovessel that have been studied to date, most attention has been paid to conventional diblock and triblock copolymers without adequate reactive sites for modification or functionalization, while some other attention has been placed on the use of complex molecules or mixed systems, which still faces tremendous unknown difficulties," Hong Tan, a professor at the College of PolymerScience and Engineering at Sichuan University in China, tells Nanowerk. "Therefore, there is an urgent need for a novel simple and powerful nanoformulation that can satisfy all the requirements to provide safe and effective delivery of various pharmaceutical agents."
To address this issue, Tan and his collaborators propose a facile "molecular engineering" strategy to integrate various desired properties into a single polyurethane macromolecule in a smart and coordinated way, where certain functionalities can be “switched on” or “turned off” as required. This approach, reported in a recent issue of Advanced Materials ("Molecular Engineered Super-Nanodevices: Smart and Safe Delivery of Potent Drugs into Tumors"), will shed new light on the design and fabrication of multifunctional nanomedicines for effective and safe cancer therapy.
Design and construction of molecular engineered super-nanodevice. (a) Schematic molecular structure of MPU. (b) Schematic presentation of C225-conjugated MPU filomicelles. The PEG outer corona and negatively charged surface provide good protection for nanocarriers in circulation (protection is “on”), while the hydrophobic core and active shell are shielded by protective corona (internalization and release are “off”). (c) Transmission electron microscopy (TEM) image of MPU immunomicelles. (d) Targeting of nanocarriers through EPR effect. (e) PH-dependant charge conversion. (f) Tumor-acidity-activated corona detachment. The surface of nanocarrier becomes positively charged and PEG corona is detached under tumor acidic environment (protection is “off”), resulting in the exposure of targeting antibody and internalizable GQA groups (internalization is “on”). (g) Nanocarriers captured and anchored to the cell surface through an antibody-receptor interaction. (h) Receptor-mediated and gemini-enhanced cellular uptake. (i) GSH-triggered intracellular drug release (release is “on”). (Reprinted with permission from Wiley-VCH Verlag)
This work demonstrates a very effective multifunctional nanocarrier which can precisely ferry highly potent and acutely toxic triptolide into tumor cells in vivo, thus significantly enhancing the drug efficacy and reducing the drug toxicity.
Polyurethanes have been well established as one of the most versatile materials used for a broad range of biomedical applications, and some have been commercially applied in clinical devices as heart valves, catheters and wound dressings1.
"Previously, we have shown the potentials of biodegradable multiblock polyurethanes with controllable biodegradation and self-assembly behaviors,2-5 cell penetrating ability6 as well as pH-sensitive properties7" says Tan. "In the present work, to further explore the clinical utility of polyurethane nanocarriers, we introduced for the first time multiple functionalities, such as long circulation, active targeting, charge-conversion, corona-detachment, cell internalization and triggered intracellular drug release, in to an all-in-one multiblock polyurethane nanosystem."
He adds that their concept is more versatile, facile and promising with respect to traditional methods for the preparation of multifunctional nanomedicines. "More importantly, our engineered nanodevices can not only deliver chemotherapeutic agents to maximize their antitumor effects, but also precisely ferry highly potent and acutely toxic drugs into tumor cells in vivo, and greatly enlarge their therapeutic windows and make them clinically applicable."
"Our study may advance the field with regard to the following aspects" explains Tan: "First, although continuous efforts have been dedicated to the development of multifunctional nanomedicines, it is still difficult to integrate all the required properties into a single carrier system. In this context, our work provides an advanced multiblock 'molecular engineering' strategy, which can incorporate various desired functions in a smart and coordinated way, and can 'switch on' or 'turn off' certain functionalities as required. This approach is facile and promising for the design and fabrication of multifunctional delivery systems for effective and safe cancer therapy."
Furthermore, the team demonstrated that this versatile nanovessel can precisely ferry anticancer agents, especially potent toxic drugs, into tumor tissue and cancer cells in vivo, thus significantly maximizing the therapeutic efficacy and reducing the drug toxicity.
"On the other hand" Tan continues, "polyurethanes have been well established as one of the most versatile materials used for a broad range of biomedical applications, and some have been commercially applied in clinic as heart valves, catheters and wound dressings, on account of their attractive physical properties, good biocompatibility and excellent molecular tailorability 1. However, the roles of biodegradable polyurethanes in the field of drug delivery remain undefined to a large extent."
In their recent work, Tan and his team show, for the first time, that multiblock polyurethanes can act as an excellent carrier platform for smart drug delivery and effective cancer treatment. Hence, their work ushers in a new era in the development of biodegradable polyurethanes for next generation nanomedicines.
The researchers point out that, to overcome the multiple physiological and cellular barriers imposed by the body, the incorporation of more functionalities and better control of the balance among different parameters are clearly needed for further optimization of their smart nanodevices.
"First" says Tan, "we will carry out studies combining other antitumor drugs, genetic materials or various imaging elements in order to attain theranostic nanomedicines for achieving personalized gene therapy and chemotherapy. Furthermore, more animal studies and preclinical trials are required to fully understand the behaviors of nanoformulations in vivo, such as biodegradation, metabolism and toxic effect."
In addition, since polymer architecture plays an important role in determining the pharmaceutical characteristics of a drug delivery agent, the further optimization of the synthesis chemistry and technology to develop polyurethanes with well-defined and well-controlled structures is of great importance for attaining desired pharmaceutical products and, more significantly, for making them easy to obtain the approval from the FDA.
"We hope, with continuous efforts made in this area, that multifunctional polyurethane nanomedicines will one day benefit cancer patients," says Tan.
1 M. Ding, J. Li, H. Tan and Q. Fu, Soft Matter, 2012, 8, 5414-5428.
2 M. Ding, J. Li, X. Fu, J. Zhou, H. Tan, Q. Gu and Q. Fu, Biomacromolecules, 2009, 10, 2857-2865.
3 M. Ding, L. Zhou, X. Fu, H. Tan, J. Li and Q. Fu, Soft Matter, 2010, 6, 2087-2092.
4 M. Ding, X. He, L. Zhou, J. Li, H. Tan, X. Fu and Q. Fu, J. Control. Release, 2011, 152, e87-e89.
5 M. Ding, Z. Qian, J. Wang, J. Li, H. Tan, Q. Gu and Q. Fu, Polym. Chem., 2011, 2, 885-891.
6 M. Ding, X. He, Z. Wang, J. Li, H. Tan, H. Deng, Q. Fu and Q. Gu, Biomaterials, 2011, 32, 9515-9524.
7 L. Zhou, L. Yu, M. Ding, J. Li, H. Tan, Z. Wang and Q. Fu, Macromolecules, 2011, 44, 857-864.