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Cancer Targeting Nanomedicine — An Opportunity for Drug Development in Asia with Emphasis on Taiwan
Bor-Fuei Huang
SynerGene (Taiwan) Therapeutics, Inc. Taipei, Taiwan
Esther H. Chang
Department of Oncology, Georgetown University Medical Center; Washington DC, USA

The current state of cancer and cancer therapy

Global cancer prevalence is on the rise largely due to the increased size and age of populations and “westernization” in lifestyles. According to the GLOBOCAN 2008 database International Agency for Cancer Research, over 40% of cancer cases are in Asia. Moreover, the largest increases in the numbers of new cancer cases is anticipated to occur in Asia; by 2030, there will likely be over 10 million new cases per year, representing a >75% increase over the comparable figure for 2008. With cancer cases growing rapidly worldwide, the cancer drug market is expected to grow correspondingly. The cancer therapeutics market is expected to be approximately USD 150 billion by 2015 [1-3].

Most of the world's cancer patients are not treated effectively. The current trend in cancer therapy is towards “targeted therapy,” although this term is not uniformly defined. The concept of “targeted therapy” includes “personalized medicine,” meaning targeting individual patients based on the molecular features of their own disease. “Targeted therapy” is also used to mean targeting of specific molecular entities. In this regard, it is noteworthy that many of the best-selling cancer drugs are monoclonal antibodies (mAbs) that each recognize its own unique cellular antigen. Examples of blockbuster mAbs are Avastin, Herceptin, Rituxin. “Targeted therapy” can also mean achieving specificity in delivery of therapeutic agents [3]. Targeting cancer cells selectively would clearly improve the therapeutic index of such drugs by making them more effective and less toxic. The bulk of the remainder of this article will deal with a proprietary technology for drug delivery that has been developed by SynerGene Therapeutics, Inc. (SynerGene).

Encapsulating and delivering a chemical (active pharmaceutical ingredient, API) in a liposome causes a modest accumulation of tumors to levels above those in normal tissues, due to what has been called the EPR effect (enhanced permeation and retention). Several liposome-encapsulated chemotherapeutic compounds are already on the market and demonstrate reduced toxicity compared to unencapsulated drug and a marginal improvement in efficacy due to this EPR effect. Without an “active targeting” mechanism, a significant portion of these liposome-encapsulated drugs will not reach cancer cells and will instead adversely affect normal tissue.

An actively tumor-targeting nanodelivery system

Those engaged in development of cancer therapeutics increasingly acknowledge that “tumor-targeting” is the key to achieving their maximal therapeutic index [4-6]. SynerGene has developed a platform nanodelivery system comprised of a self-assembling, cationic liposomal nanoparticle, bearing a targeting molecule that result in the nanoparticle homing to cellular receptors, e.g., the transferrin receptor (TfR), which is elevated in number on the surface of tumor cells [6-10]. When systemically administered, this nanocomplex can efficiently and selectively deliver molecular therapeutics, including plasmid DNA [11-13], si/miRNA [14-16], imaging agents [17-21], small molecules [22], and chemotherapeutic agents to primary tumors and metastatic lesions. Nanocomplex delivering imaging agents results in a marked improvement in detection of minute metastatic lesions [18]. Delivery of certain molecular therapeutics has been shown to sensitize human tumors in mouse xenograft models to radiotherapy and chemotherapy [23-24].

SynerGene's nanodelivery system has been shown to: (1) deliver therapeutics specifically to tumors (primary and metastatic lesions) while bypassing normal cells and tissues; (2) deliver agents efficiently i.e., a high percentage of injected dose reaches the target; (3) achieve the desired anti-tumor effect with low toxicity; and (4) target both stem cells and non-stem cell populations within the tumor. Because the TfR is elevated in many cancer types, this delivery system has the potential to be effective for a wide spectrum of cancer indications: e.g., pancreatic, brain, lung, prostate, breast and colon have all been successfully targeted in xenograft models. SynerGene's nanocomplex (Figure 1) is composed of three components: the payload i.e., the active molecule to be delivered; a positively charged liposomal shell which encapsulates and protects the payload; and a moiety on the surface of the liposome that targets a cellular receptor that is overexpressed on cancer cell surface.

This nanodelivery system, carrying the human tumor suppressor gene p53 as payload (in a product termed SGT-53), has now completed a Phase I clinical trial as a single agent [25]. SGT-53 utilizes a single chain mAbs fragment recognizing the TfR as its targeting moiety. The production of the basic reagents comprising this nanocomplex is cGMP certified, and the complex has been shown to be well tolerated in patients at anticipated clinical doses. Three Phase Ib/II clinical trials have been planned to evaluate SGT-53 in combination with standard treatments in patients with pancreatic, brain, or lung cancers.

Figure 2 depicts the mechanisms through which the payload carried by the nanocomplex is delivered and released into the cancer cell. First, the targeting moiety on the nanoparticle engages the TfR. Receptor-mediated endocytosis leads to internalization of the receptor-nanoparticle complex into the endosomal compartment of the cell. In the acidic environment of the late endosomes, the nanoparticle dissociates from the TfR delivering its payload intracellularly. It is clear in the case of gene payloads (like p53 in SGT-53) that the payload reaches the nucleus for expression. The TfR, once freed from the nanoparticle is recycled to the surface of the cell and reutilized for subsequent nanoparticle uptake.

SynerGene's preclinical data with tumor-targeting nanoparticles

We herein provide two representative experiments demonstrating the utility of SynerGene's proprietary delivery system--one encapsulating chemotherapeutic agent Temozolomide (TMZ), and the other encapsulating tumor suppressor gene p53.

TMZ is an alkylating agent often used in treatment of brain tumors most of which have a poor prognosis [26]. Brain tumors were induced in athymic mice by intercranial inoculation of human glioblastoma cells modified so as to express the firefly enzyme luciferase. The relative size of the implanted tumor can be determined by assessing the output of light from the luciferase enzyme. Various treatment regimens were begun 7 days after the same number of tumor cells injected. Mice were treated via tail vein injection of unencapsulated TMZ or tumor-targeting liposomes containing TMZ (scL-TMZ). All untreated mice were killed by the growing brain tumor within 30 days [the image of the untreated mouse (left panel) in Figure 3 was taken at 24 days]. The images of the mice treated with either free TMZ (middle panel) or scL-TMZ (right panel) were taken on day 51. Both of these treatments significantly lengthened the lives of the mice with brain tumors but the encapsulated TMZ was clearly superior to free TMZ. The efficacy of the tumor targeting liposomes containing TMZ demonstrate that the nanoparticle is capable of crossing the blood brain barrier.

Figure 4 shows the survival curves of the athymic mice bearing a human tumor that represents a model for lung cancer. The chemotherapeutic agent docetaxel (Taxotere) given as a single agent provided little benefit in terms of survival suggesting that this particular tumor is highly chemoresistant. The systemic administration of scL/p53 or Tf/p53 via the tail vein in combination with Taxotere significantly extended the lifespan of the animals beyond that of untreated mice, or those treated with Taxotere-only or the non-targeted lipoplex plus Taxotere.

Drug development in Asia and the potential for Taiwan

With its growing populations, increasing average age, and improving economic status, Asia is an emerging pharmaceutical market. Several Asian governments (including Taiwan) have gone on record with enhanced commitments to healthcare; this should result in higher future consumption of pharmaceuticals. The Asia-Pacific region is ranked by Business Monitor International in terms of the risk/reward rating for pharmaceutical development behind only Western Europe, and the Asia-Pacific is ranked higher than emerging Europe, the Americas, and the Middle East/Africa [27]. Within Asia, Japan ranks as the clear leader in terms of the BMI risk/reward rating. However, the Chinese-speaking areas of China, Singapore, Taiwan, and Hong Kong are also highly ranked. Based on their existing expertise and reputation for quality, Taiwan-based companies appear to be well positioned to tap the very large pharmaceutical markets of these Chinese-speaking jurisdictions.

Cost estimates for drug development suggest that it takes an average of over 10 years and close to USD1 billion to bring a drug to market from beginning to end. This significant investment of time and money makes many Asian pharmaceutical companies reluctant to venture into developing new drugs from the point of discovery in basic research. However, many countries in Asia (including Taiwan) are technically capable and highly competitive in manufacturing small molecule APIs. By encapsulating a generic, already approved API, a company could develop a new pharmaceutical product in shorter time, with less financial investment, and with fewer regulatory hurdles. From an investment perspective, these factors equate to reduced risk. Because the encapsulated product could have patent protection, this approach would allow realization of high value with extended product life compared to the unencapsulated API without necessitating a totally new chemical entity The addition of tumor-targeting as described here would likely have the added advantage of product with substantially improved therapeutic index (higher efficacy plus lower toxicity). For all these reasons, SynerGene is actively seeking an appropriate partner in for the dynamic Asian market with preference for a partner from Taiwan.

About the Authors

Dr. Esther H. Chang is a professor of Oncology and Otolaryngology at Georgetown University Medical Center, USA. Currently, she is President of the American Society for Nanomedicine and is the founding scientist of SynerGene Therapeutics, Inc.

Dr. Bor-Fuei “Apo” Huang is the CEO of SynerGene (Taiwan) Therapeutics, Inc. and the Secretary General of Taiwan Bio Industry Association. Dr. Huang received his Ph.D. from Rutgers University and MBA from the Pennsylvania State University, and had held several senior positions at the Development Center for Biotechnology, Taiwan.


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