http://informahealthcare.com/drd ISSN: 1071-7544 (print), 1521-0464 (electronic) Drug Deliv, 2015; 22(3): 258–265 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10717544.2014.892545

CRITICAL REVIEW

Application of traditional Chinese medicine preparation in targeting drug delivery system Wei Xu, Feng J. Xing, Kai Dong, Cuiyu You, Yan Yan, Lu Zhang, Guilan Zhao, Youliang Chen, and Ke Wang

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School of Pharmacy, Health Science Center, Xi’ an Jiaotong University, Xi’an, China

Abstract

Keywords

Targeting drug system (TDS) or targeted drug delivery system (TDDS) is a new kind of drug delivery system which could make drug to be directly concentrated on the target site with high curative effects and low side-effects. As the quintessence of Chinese culture, traditional Chinese medicine (TCM) has a large advantage in many disease clinical treatments, especially in cancer, hypertension and many other intractable diseases owing to their low toxicity and side-effects relative to western medicine. This article reviews literatures on development of TCM-targeted preparations which were published in the past 10 years. TDS including active-targeting, passive-targeting and physical-chemical-targeting preparations were introduced through domestic and overseas literatures to reveal the unique advantages of TCM-targeting preparations in drug delivery system. In this article, we have reviewed some kinds of TCM-targeting preparations and indicated that great attention should be paid to the research on the TCM-targeting preparations.

Clinical treatments, pharmacological effects, targeting drug delivery system, TCM-targeted preparations, traditional Chinese medicine

Introduction The concept of targeted agents was proposed earlier by Ehrlichp in 1906. The targeted agents, also called targeted drug delivery system (TDDS), refer to the drug carrier that selectively concentrates on the medicine target area (Sudimack & Lee, 2000). They can greatly increase the dose of drug on the target site. Simultaneously, decrease the using time of drug and reduce its side-effects. At present, there are some targeted agents, and the use of each of these has distinct but interrelated goals (Chilkoti et al., 2002; Krishnaiah et al., 2002; Wang et al., 2003; Patri et al., 2005; Bareford & Swaan, 2007; Sutton et al., 2007). With the development of biomedical science, biomaterials science and molecular biology, the investigation of TDDS now is become a research hotspot. Great attention should be paid to the research of targeting preparations, especially its application for anti-cancer research area (Brannon-Peppas & Blanchette, 2004; Nasongkla et al., 2006; Liu et al., 2007; Peer et al., 2007). Western medicine have been extensively studied and applied clinically in the pharmacy field. It has the benefits of rapid-action profile, high bioavailability, but easily introduce the high side-effects at the same time. On the contrary, traditional Chinese medicine (TCM) effects more slowly, yet has stable curative effect and less side-effect (Howes & Houghton, 2003; Normile, 2003; Drasar & Moravcova, 2004; Li et al., 2004). TCM, which

Address for correspondence: Ke Wang, School of Pharmacy, Health Science Center, Xi’ an Jiaotong University, Xi’an 710061, China. Tel: +86 29 82655382. Fax: +86 29 82655382. E-mail: [email protected]

History Received 17 January 2014 Revised 5 February 2014 Accepted 5 February 2014

incorporates the therapeutic use of herbs and other natural products, has been embedded in many cultures for thousands of years. In spite of this, TCM is still in the basic research stage nowadays. TCM comprises medicinal products from plants, animals and minerals, acupuncture, and other practices. They are some of our oldest alternative and complementary medicines and their ever-increasing use is a good indication of the public interest in such medicines (He et al., 2005; Cai et al., 2006; Stickel & Schuppan, 2007). Currently, there is a tremendous interest in the western world in TCM. TDDS of TCM using various carriers is an effective way to enhance the bioavailability of drug and improve their curative effect (Yang, 2004; Chiu et al., 2009; Parekh et al., 2009). TCM drugs could be concentrated directly to the organs, cells, lesion tissues or cell structures after the effective transmission by these carriers. They could increase the drug concentration on lesions higher than that of other normal parts (Allen & Cullis, 2004; Efferth et al., 2007). On the other side, prominent examples of isolated therapeutics derived from Chinese plants are established in modern medicine without being treated with the same reluctance as traditional herbal products, including the CNS stimulator ephedrine (Ephedra sinica), the ion channel blocker tetrandrine (Stephania tetrandra), the anti-malarial artemisinin (Artemisia annua), and the well-known anticancer agents camptothecin from Camptotheca acuminate or paclitaxel from Taxus chinensis and so on (Efferth et al., 2007). Targeted TCM among these mentioned above could decrease the using time of drug and largely reduce the toxic side-effects. Table 1 summarized the typical example of targeting TCM preparations in recent years.

TCM-targeting preparations

Ganta et al., 2008

Hua et al., 2010 Wang et al., 2012

Li et al., 2009a Paciotti et al, 2006

Potineni et al, 2003

Visaria (2006) Potineni (2003)

Tumor

Tumor Tumor

Vascular dementia Tumor

Tumor

Tumor Tumor

R8- modified liposomes

Soybean lecithin, cholesterol PEG Dioleoyl trimethyl-ammonium propane, cholesterol Liquid paraffin, gelatin Soybean lecithin

Styrene Itaconic acid, divinylbenzene

Polyethylene glycol Colloidal gold Poly(b-amino esters), 4,40 -trimethyldipiperidine 1,4-butanediol diacrylate

Water in oil emulsion method

solvent evaporation technique Controlled solvent displacement method

Physical Chemical Targeting TCM preparation

Modified-microemulsion Surface modification microspheres nanospheres Magnetically Targeting Microspheres

Long-circulating liposomes Immuno liposomes

Glycolipid-modified liposomes Active Targeting TCM preparation

Thermo-therapy gold nanoparticles pH targeting polymeric nanoparticles

Liang et al., 2006 Tumor Nano-particles

Two-step emulsification Ultrasonication

Tamilvanan (2009). Cao et al., 2009 Liver tumor, etc Colon O/W emulsions PCL-PEG-PCL copolymers

Emulsification method Oil-water emulsion solvent evaporation method Emulsion/solvent evaporation technique Efficient/simple packaging method Ethanol injection method Film dispersion method

Liposomes Passive targeting TCM preparation

Emulsion Micro-spheres

Soybean lecithin, cholesterol Film dispersion method

g-PGA-PLA block copolymers

Dai et al., 2011 lung

Carrier materials Preparation method Categories

Table 1. Studies on the targeting preparation of TCM.

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Target site

Reference

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Figure 1. Enhanced permeability and retention (EPR) effect key: long-circulating drug carriers: (1) penetrate through the leaky pathological vasculature (2) into the tumor interstitium (3) and degrade there, releasing a free drug (4) and creating its high local concentration.

Drug targeting offers enormous advantages but is highly challenging and extremely complicated. Increased knowledge on the cellular internalization mechanisms of the carriers is crucial for improving their efficacy, site-specific delivery. Figure 1 shows that the drug delivery system has initially been designed to take advantage of the enhanced vascular permeability present at disease sites. It leads to the much more complex targeting preparations of TCM (Chen & Chen, 2003; Xie & Xiong, 2008; Utreja et al., 2010). At present, TCMtargeted agents are still in the exploratory stage and many problems need to be solved. From the other way, targeted drug system including active-targeting, passive-targeting and physical-chemical-targeting preparations were introduced through domestic and overseas literatures to reveal the unique advantages of TCM-targeting preparations in drug delivery system. Many researches on the different drug delivery carriers were got involved profoundly to understand the targeted TCM drug delivery system. According to the classification of drug carriers, this article gives an overview on the research progress of three ways of targeting TCM drug delivery system in recent years.

Passive-targeting TCM preparation Passive-targeting preparation, also called natural targeted agents, is the preparation that uses the drug carrier to make the drug naturally swallowed by macrophage through physiological processes (Li et al., 2009a). Once the drug-loaded particle reached the circulatory system, it was up taken by mononuclear phagocyte system, especially Kupffer cell from liver. This kind of targeting preparation comprises of liposome, microspheres, nanocapsules, nanospheres, etc (Panyam & Labhasetwar, 2003). The considerable attractiveness of TCM during the past years raised the interest of phytochemistry and pharmaceutical biologists to investigate the pharmacological basis of TCM. Many active ingredients had been exploited in some TCM with favorable curative effect. Numerous drug carriers have been developed through exploration of pharmaceutics, combining with ethno-pharmacology and traditional medicine. Therefore, targeting preparation of TCM will play a strong role in the field of pharmacology, clinical medicine, etc (Allen & Moase, 1996; Kaneda, 2000; Vasir et al., 2003; Peppas & Blanchette, 2004; Xiong et al., 2005; Liang et al., 2006;

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Chang & Chu, 2008; Tamilvanan, 2009; Dong et al., 2010; Graziose et al., 2010; Qi et al., 2011).

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Liposomes Liposomes, which are biodegradable and essentially non-toxic vehicles, can encapsulate both hydrophobic and hydrophilic materials, and are utilized as drug carriers in drug delivery system. Compared to nanocapsules and microspheres, it has more advantages in therapy of cancer and hepatic disease. Due to the similar composition to cytomembrane, liposomes can easily be absorbed by cell, thus enhance the curative effect and reduce the adverse action. In order to improve its targeting therapeutic effect, in recent years, researchers dedicated to investigate new liposomes, such as immuoliposomes, long-circulating liposomes and glycol-lipid-modified liposomes, etc. The cholesterol and phosphor-lipid are the basic materials of general liposomes. It had been widely used in the pharmaceutics as targeting drug carrier, including various TCM drugs, such as curcumin, panax notoginseng saponins (PNS), tanshinone, etc. PNS liposomes were prepared by Shen & Fang (2004) using thin film dispersion method. Its encapsulation rate is 78.5%, with the uniform particle size of 1.5 um. Li et al. (2009c) designed and characterized quercetin-loaded solid lipid nanoparticles, and clarified the absorption mechanism of QT-SLNs and evaluate the potential of using solid lipid nanoparticles as an oral delivery carrier for poorly water-soluble drugs.

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Microspheres Microspheres are the particle dispersion of drug scattering or absorbing in the molecular and polymer matrix. A great number of carrier materials could make microspheres. They are mainly divided into natural molecular microspheres such as starch, albumin, gelatin and chitosan microspheres, etc. and polymer microspheres including poly-lactic acid, etc (Li et al., 2009a). According to their biodegradability, they can be divided into biodegradable and non-biodegradable microspheres. So far, a series of TCM active ingredients, such as camptothecin (CPT) (Hatefi & Amsden, 2002), etoposide (Hanna et al., 2006), tetrandrine (Fu et al., 2002) and so on has been made into microspheres for targeted agents. Dai et al. (2011) had prepared a new kind of CPT-loaded PCEC microspheres for the treatment of colorectal peritoneal carcinomatosis and tumor growth in mice. CPT is a wellknown anti-cancer agent which was originally isolated from camptotheca acuminate. It has shown significant anti-tumor activity to lung, ovarian, breast, pancreas and stomach cancers. Its clinical application is greatly limited due to its extremely water insoluble and side-effects, respectively. In this research, we could find that a significant decrease in the number of tumor nodes was observed in group treated with CPT-loaded PCEC microspheres. Therefore, this microspheres preparation was considered potentially useful to treat the abdominal metastases of colon carcinoma. Nanoparticles

Emulsion Emulsion refers to a non-uniform dispersion of potions system that is comprised of two kinds of the liquid phase unable to dissolve each other. Generally, emulsion is comprised of water phase, oil phase and emulsifier, each of them is indispensable (Li et al., 2009a). They are divided into normal emulsion (0.1–100 mm), submicroemulsion (0.1–1 mm) and nanoemulsion (50.1 mm) according to their size of emulsion droplet. The targeting characterization of emulsion is the affinity to lymph. As a rule, oily drugs or lipophilic drugs were made into O/W or O/W/O emulsion, whereas the watersoluble drugs should be made into W/O or W/O/W emulsion, that can be easily concentrated in the lymphatic system by intramuscular or subcutaneous injection. Nevertheless, the size of the emulsion particles has a huge impact on its target distribution. Tamilvanan Shunmugaperumal reviewed the formulation of multifunctional oil-in water nanosized emulsions for active and passive targeting of drugs to otherwise inaccessible internal organs of the human body (Tamilvanan, 2009). In the review, author lists three kinds of generation nanosized emulsions and compares their advantages and disadvantages in pharmacology and clinical applications, respectively. Yue et al. (2008) investigated the preparation, characterization and pharmacokinetic evaluation of puerarin submicron emulsion. Detailed results displayed that puerarin submicron emulsion was stable for a period of 3 months. And the elimination rate of puerarin emulsion was significantly decreased compared with the puerarin group after intravenous administration of puerarin emulsion. Meanwhile, the biological half-life and the mean retention time of puerarin emulsion were markedly increased.

Nanoparticles, with a diameter of 10–500 nm, are drug-loaded particles prepared by taking natural polymer or synthetic chemicals as the carrier. Active ingredient (drug, gene, etc) could be embedded or absorbed in the internal or surface of particles. The solubility and pharmacokinetics of drug was largely improved, and in some cases, reduced the serious toxicity and side-effects. Nanoparticles have passive-targeting ability on the liver, spleen and marrow. For all the applications by nanoparticles in pharmaceutics, it is the best available way to tumor and cancer therapy. The major carrier materials of nanoparticles are synthetic biodegradable high molecular polymer and natural polymer. Xiong et al. (2005) reported the preparation, characterization, pharmacology and toxicology of triptolide-loaded nano drug delivery systems in the past 3 years in their group. This investigation either improve the solubility of triptolide or show promising potentials in controlled release, targeted drug delivery and avoiding the toxicity at non-target site. Liang et al. (2006) developed paclitaxel-loaded formulations using a novel type of self-assembled nanoparticles composed of block copolymers synthesized by poly(g-glutamic acid) and poly(lactide). The biodistribution and anti-tumor efficacy of the prepared nanoparticles were studied in hepatoma-tumor-bearing nude mice. And this investigation indicated that the prepared nanoparticles may be used as a potential drug delivery system for the targeted delivery to liver cancers. Lin et al. (2007) prepared chitosan nanoparticles loading berberine and investigated the characteristics of in vitro release of the prepared nanoparticles. The encapsulation ratio of berberine chitosan nanoparticles was 65.4 ± 0.7%, and the total drug release degree was 56.8 ± 1.7%, respectively.

TCM-targeting preparations

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Active-targeting TCM preparation Active-targeting preparation, including modified drug delivery carrier, ligand–receptor system, immunomicelles, prodrug, could concentrate the drug directly to the target site and get preferable curative effect. For example, because the modification of the surface of drug-loaded particles could not be identified by macrophage, specific ligand was connected in order to combine the receptor of target cell, monoclonal antibody was linked to immunomicelles refraining from being absorbed by macrophage. Meanwhile, it could prevent the concentrated set in the liver and change the natural distribution in the body to reach specific target site (Li et al., 2009a). On the other aspect, the drug was modified into pro-drug would give full curative effect in specific target site. Generally, the size of particle keeps at 4 mm to avoid being held by blood capillary. According to the carriers, activetargeting preparation can be divided into modified liposomes, micro-emulsions, microspheres and nanoparticles, etc. (Bromberg et al., 2003; Cheng et al., 2007; Homhuan et al., 2007; Bakowsky et al., 2008; Mccarron et al., 2008; Min et al., 2008; Cao et al., 2009; Shen et al., 2009; Werle et al., 2009; Weber, 2010; Botella et al., 2011; Devarajan & Ravichandran, 2011). Tian et al. (2010) using the specific receptor–ligand combination principle on the surface of tumor cells, established a liver-targeted drug delivery carrier, which was composed of chitosan/poly(ethylene glycol)-glycyrrhetinic acid nanoparticles. The drug delivery carrier was prepared by an ionic gelation process, in which glycyrrhetinic acid acted as the targeting ligand. Glycolipid-modified liposomes Liposomes with different glycosyl combining on its surface can get different distribution in vivo. For example, liposomes uptake by K cell when carrying mannose residues and uptake by liver parenchymal cells when carrying galactose residues. It is intensively distributed in the lungs when carrying derivatives of amino mannose. Homhuan et al. (2007) explored new packaging method of mycobacterial cell wall using octaarginine-modified liposomes in order to enhance absorption and immunostimulatory activity of dendritic cells. This investigation is achieved by incorporating mycobacterials CW into

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liposomes and attaching arginine octamers (R8) to the liposome surface, which indicated that R8-modified liposomes with mycobacterial CW incorporation should have tremendous potential as immune-potentiating agents. Long-circulating liposomes After the suitable modification on the surface of liposomes, swallowing by macrophage was avoided and prolonged the circulating period in vivo. As a drug carrier, long-circulating liposomes can be applied in clinical TDDS, particularly to the tissues or organs aside from liver and spleen. The development of long-circulating, reticuloendothelial system (RES) liposomes has played a stronger role in the progress of contemporary pharmacology. Wang et al. (2006) prepared brucine long-circulating liposomes (BLCL) by means of optimization screening and evaluated its quality. BLCL were prepared by the technique of ammonium sulphate gradients with ethanol injection. The poly(ethylene glycol) (PEG) was added to modify the membrane of the liposomes. With the mean particle size of 120 nm, the entrapment efficiency of BLCL was up to 93.72%. And it had good stability in 4  C, which indicated that this preparation of BLCL is practicable and the pharmaceutical characterization showed stable. Immunoliposomes Some antibodies conjugated on the surface of liposomes were called immunoliposomes. And they can distinguish the target cell, further up enhancing the site-specifically targeting of liposomes. As shown in Figure 2 (Manjappa et al., 2011), PEGylated liposomes were prepared to conjugate intact or derivatized monoclonal antibodies with high degree. The layer of functional PEG derivative protects liposomes from being identified, and taking by opsonin in the blood, which slowed down the clearance of liposomes and prolonged the presence of drug or effective time in blood. Chen et al. (2010) designed a truncated human basic fibroblast growth factor peptide (tbFGF), which was attached to the surface of cationic liposomal doxorubicin (LPs-DOX) and paclitaxel (LPs-PTX) via electrostatic force, respectively. The tbFGF-modified liposomes were then characterized and examined the internalization of DOX in tumor cells. The in vivo biodistribution

Figure 2. Preparation of PEGylated liposomes and conjugation of intact or derivatized monoclonal antibodies (PEGylated immunoliposomes) through various functionalized PEG derivatives.

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and anti-tumor efficacy of them in C57BL/6J mice-bearing TRAMP-C1 prostate carcinoma and B16 melanoma were evaluated, respectively. The tbFGF-LPs-DOX significantly improved the uptake of DOX in TRAMP-C1, B16 and HUVEC cells. Biodistribution study in B16 tumor-bearing mice showed that tbFGF-LPs-PTX achieved 7.1-fold (72.827 ± 7.321 mgh/L versus 10.292 ± 0.775 mgh/L, mean ± SD, p50.01) accumulation of PTX in tumor tissue than those of free PTX. This work indicated that tbFGF-LPs achieved favorable tumor-targeted drug delivery and showed the excellent anti-tumor effect due to specific binding and internalization endothelial cells of tumor vessels and tumor cells via tbFGF peptide.

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(A)

Mix liquor

free radical polymerization dispersed phase emulsifier

(B)

magnetic nanoparticles

continuous stirring

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Modified-microemulsion Microemulsion polymerization has been quite actively studied since 1980. Small latex particles of less than 50 nm with molecular weights of polymers exceeding 1 million can easily be obtained from microemulsion polymerization. According to the size of particles, microemulsion can be classified into ordinary emulsion (0.1–100 mm), submicroemulsion (100–600 nm), nanoemulsion (10–100 nm), etc. The last one could not easily be influenced by serum albumin, thus it maintains long life in the circulating system. Adding the PEG-modified phosphatidyl ethanolamine into water phase to make the microemulsion with the uniform size of 44 nm, it could reduce the clearance rate in blood after intravenous injection and prolong its half-life. Surface modification of microspheres and nanospheres Microspheres and nanospheres are the matrix which is spherelike or spherical substance based on polymer materials, and drugs dissolved or dispersed uniformly in them. Surface of microspheres and nanospheres can be modified to improve their active targeting in vivo and extend their detention time in the blood. With the ultrasonication method was employed to prepare solid lipid nanoparticles (SLN), Li et al. (2006) incorporated the model TCM of tetrandrine (TET) into SLN. The TET-loaded SLN (TET-SLN) were spherical with the size of 157.3 ± 8.2 nm. The entrapment efficiency (EE%) was determined with the sephadex gel chromatogram and HPLC, and up to 90.59% of TET was incorporated.

Physical and chemical targeting TCM preparation During the last several years, targeted drug delivery has been developed significantly and made some drugs; especially anticancer agents release and accumulate to a high concentration only at sites where tumors reside, and thus considerately reducing their toxicity on normal tissues. Various strategies, such as antibody-, receptor-, magnetic-, pH-, and thermotarget, can be used for targeted drug delivery. These physical and chemical methods for making targeting preparation to play the pharmacodynamics at the specific site are called physical and chemical targeting preparation (Ganta et al., 2008; Li et al., 2009b). Magnetically controlled drug targeting is one of the various possibilities of drug targeting. This technology is based on binding established some drugs with ferrofluids that

heat initiated

emusilfication

deionized water

A B

Synthesis of P(St-IA-DVB) microspheres Synthesis of MNPSID microspheres

Scheme 1. Schematic illustration of synthesis of P(St-IA-DVB) microspheres and MNPSID microspheres, respectively.

concentrate the drug in the area of interest by means of magnetic field. Then the drug desorbs from the ferrifluid and enfolds its mechanism of action. Some active ingredients isolated from TCM drug, can effectively kill cancer cells, and can be used for anti-cancer agents for tumor therapy (Lu¨bbe et al., 2001; Neuberger et al., 2005; Arruebo et al., 2007; Chertok et al., 2008; Hua et al., 2010). In some cases, combining the magnetic technology mentioned above can enhance the targeting abilities of TCM drug and improve the application in tumor therapy and anti-cancer treatment. Wang et al. (2012) prepared a series of P(Styrene-itaconic aciddivinylbenzene) P(St-IA-DVB) microspheres via water-in-oil emulsions method. The magnetic nanoparticles (i.e. Fe3O4) coated tightly on the surface of P(St-IA-DVB) microspheres were prepared in water with a continuous stirring. Scheme 1 shows the schematic illustration of synthesis of P(St-IA-DVB) microspheres and MNPSID microspheres, respectively. In vitro drug release investigation indicated that these magnetic nanoparticles-coated P(St-IA-DVB) (MNPSID) microspheres might have great potential application in magnetically targeted and thermal therapy. Hua et al. (2010) synthesized a novel of non-toxic drug nanocarrier containing carboxyl groups which successfully developed by mixing magnetic nanoparticles (MNPs) of Fe3O4 with the watersoluble poly-aniline derivative poly[aniline-co-sodium N-(1-one-butyric acid) aniline] (SPAnNa) and doping with HCl aqueous solution to form SPAnH/MNPs shell/core (Scheme 2). It can be used to effectively immobilize the hydrophobic drug paclitaxel (PTX), which was isolated from Taxus chinensis, thus enhancing the thermal stability and water solubility of drug. The cell experiment indicated that this magnetically TDDS provided more effective treatment of prostate cancer cells using lower therapeutic doses and thus with potentially fewer side-effects. With the invention of large-scale hyperthermia instruments and the wide use of hyperthermia, thermal targeting has become much easier to implement and more precise to control

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Scheme 2. Schematic illustration of synthesis of bound-PTX.

(Johannsen et al., 2006; Paciotti et al., 2006; Sayed et al., 2006; Visaria et al., 2006; Yang et al., 2007, 2009; Liu et al., 2008; Shen et al., 2008; Li et al., 2009d). Thermal targeting has the following obvious advantages: (1) Compared to other techniques such as active targeting, it can be applied on a wide spectrum of cancer types as it relies on local heating to confine the release of drugs. (2) Hyperthermia has a particular advantage of synergetic effects to kill malignant tumor cells when combine with chemotherapies. (3) Hyperthermia increase the permeability of tumor vasculature preferentially when compare with that of normal vasculature, further promoting the delivery of drugs to tumors. Visaria et al. (2006) used a newly developed nanoparticles delivery system consisting of 33 nm PEG-coated colloidal gold nanoparticles with incorporated TNF-a payload to maximize tumor damage and minimize systemic exposure to TNF-a. The combination treatment of SCK tumors in vivo reduced the in vivo/in vitro tumor cell survival to 0.05% immediately following heating and to 0.005% at 18 h after heating, suggesting vascular damage-mediated tumor cell killing. Since the nanotechnology applied to biological problems represents an emerging field with the potential to offer extremely sensitive diagnostics and targeted cancer therapies, Paciotti et al. (2006) specifically discussed the development of colloidal gold-based drugs that were designed to target the delivery of TNF and paclitaxel to solid tumors. Many therapeutic anti-cancer drugs, while pharmacologically effective in cancer treatment, are limited in their clinical applications by serious toxicities. Stimuli-responsive polymeric micelles as nano-sized drug carriers have been considered for the controlled release of drug into tumor tissue, with temperature, ultrasound and pH used to trigger drug release from polymeric micelles. It is acknowledged that tumor tissues have a more acidic environment, due to lactic acid produced by hypoxia and by acidic intracellular organelles. Therefore, change of pH at tumor tissue is useful for tumor therapy. Potineni et al. (2003) developed and

characterized a pH-sensitive biodegradable polymeric nanoparticles system for tumor-selective paclitaxel delivery. Paclitaxel release study shows that approximately 10% was released in the first 24 h, 80% after 3 d, and the entire content was released in approximately 5 d. This investigation demonstrates that PEO-modified poly-1 nanoparticles could provide increased therapeutic benefit by delivering the encapsulated drug to solid tumors.

Prospects TCM comprises medicinal products from plants, animals and minerals, etc. It is frequently regarded with some skepticism by western academic medicine, because it represents a holistic approach pointing to the entire human body, while western science and medicine is focus on mechanisms. Rather than analyzing the patient entirely, it is only the disease that is analyzed at the cellular, molecular and pharmacological level. On the other side, scientific evidence of efficacy and safety is frequently missing, and quality management needs to be improved. A number of problems need to be solved for targeting preparation of TCM such as drug-loading rates, stability of preparations, metabolism dynamic and evaluation of qualities, etc. At present, the design, synthesis and quality evaluation of TDDS are only fit for single ingredient of TCM, not suitable for compound TCM preparation owing to its complex composition and physicochemical property. Therefore, research on TDDS of TCM is still at the exploratory stage. In order to achieve a satisfaction purpose, pesticide effect of TCM and its mechanism research needs to be strengthened; meanwhile, the investigation of its physicochemical, biopharmaceutics and pharmacodynamics also should be enhanced. In addition, more attention should be paid to the research on the carrier materials in order to develop more suitable specific-site targeting preparation that could enhance the activity of drugs and reduce the toxicity of them. Thus, it is

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necessary to improve the modification of carrier materials for drugs to change the passive targeting to active targeting, indeed to improve the curative effect of targeting preparation. The investigation of TCM targeting preparation is the most important content of modernization of TCM. With the deep study of pharmacology, biopharmaceutics, pharmacodynamics and pharmacokinetics, the research level of the pharmacy agents will be able to reach a new height and get a rapid development.

Declaration of interest This project was supported by National Science Foundation of China (81173024 and 81227802) and Fundamental Research Funds for the Central University (xjj2013054).

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