Research Progress on Targeted Traditional Chinese Medicine Formulations-Liaoning Chaohua Pharmaceutical Co., Ltd.

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Research Progress on Targeted Traditional Chinese Medicine Formulations

Release Date:

2021-03-12

Research Progress on Targeted Traditional Chinese Medicine Formulations

Abstract: Targeted formulations, also known as targeted drug delivery systems, concentrate drugs at the site of disease and maintain a sustained therapeutic concentration at the target site for a specified duration, thereby reducing the required dosage. This approach can, to a certain extent, decrease the incidence of adverse drug reactions, enhance drug safety, and improve patient compliance. Consequently, targeted formulations have garnered widespread attention in the field of pharmaceutics. This review summarizes recent research on the application of traditional Chinese medicine (TCM) targeted formulations, focusing on advances in passive targeting, active targeting, and physicochemical targeting. The aim is to provide a reference for further research on the application of targeted formulation technologies in TCM targeted delivery systems.

Traditional Chinese medicine comprises a vast array of formulations, most of which are natural products derived from plants, animals, and minerals, with highly complex chemical compositions. As research into the bioactive constituents of TCM has deepened, natural compounds from TCM or their derivatives have yielded promising results in both new-drug development and clinical applications. These natural constituents exhibit advantages such as high efficacy, low toxicity, and multi-target activity; however, their limited solubility and poor stability result in low bioavailability, coupled with extensive target engagement and suboptimal tissue-specific distribution, thereby restricting their clinical utility.

Targeted formulations, also known as targeted drug delivery systems, utilize carriers to achieve selective accumulation of drugs at the site of disease. The site of disease is referred to as the target site, which may be an organ, tissue, cell, or a specific intracellular target. Traditional Chinese medicine–based targeted formulations are prepared by extracting and isolating active constituents or effective fractions from traditional Chinese medicinal materials and then formulating them into various dosage forms using different carrier systems. ^[1] It exhibits pharmacological specificity, minimal adverse effects, and high bioavailability. The modern concept of targeted delivery aligns remarkably with the traditional TCM theories of “guiding the meridians” and “directing drugs to specific organ systems,” both of which emphasize the ability to direct a drug to its intended target—just as Wu Jutong stated in his “Medical Treatise on Treating Diseases”: “The use of ‘meridian-guiding’ agents in pharmacology is akin to employing a guide for those who do not know the way.” Moreover, contemporary pharmacological and pharmacokinetic studies have provided empirical support for the similarity between TCM’s meridian-guiding theory and modern targeted-delivery principles. Existing research has demonstrated that borneol possesses brain-targeting properties and can enhance the cerebral distribution of other drugs. ^[2] In formulas such as Angong Niuhuang Wan, borneol assists bezoar and musk in “penetrating the collateral channels from within,” thereby facilitating their guiding action. Modern pharmacological studies have also demonstrated that borneol can enhance the brain accumulation of various drugs, including quercetin and geniposide. In recent years, targeted formulations of active constituents from traditional Chinese medicine have garnered particular attention. As research on targeted delivery systems continues to advance and related fields keep expanding, targeted therapy with TCM has opened up new avenues for the treatment of complex and refractory diseases. Based on the different mechanisms of action of targeted drug-delivery systems, these formulations can be classified into three categories: passive-targeted, active-targeted, and physicochemical-targeted preparations. In recent years, significant progress has been made in developing TCM-based targeted formulations using microspheres, liposomes, nanoparticles, magnetic targeting systems, and thermosensitive targeting systems. Moreover, the emergence of novel materials is expected to make passive-targeting carriers safer, more precise in their targeting, and more effective, thus heralding a very promising future for targeted drug-delivery systems.

1 Passive targeting formulation

Passive targeting formulations, also known as natural targeting formulations, are taken up by macrophages of the mononuclear phagocyte system and, through normal physiological processes, deliver the drug to the target site, thereby achieving targeted delivery. ^[3] The primary difference between this approach and passive-targeting formulations is that the former do not incorporate ligands with specific binding properties on their carrier particles.

1.1 Microsphere

Microspheres typically have particle sizes ranging from 1 to 250 μm and constitute a particulate dispersion system in which drugs are dispersed or adsorbed within a polymeric matrix. ^[4] is one of the commonly used drug carriers with targeted delivery capabilities, typically administered by injection or oral intake. By controlling the particle size of the microspheres, their targeting specificity for different target sites can be achieved. Generally, microspheres smaller than 7 μm are phagocytosed by macrophages in the liver and spleen; microspheres ranging from 7 to 10 μm, as well as those with larger diameters, are usually mechanically trapped in the pulmonary capillary bed, thereby concentrating the drug in the lungs. ^[5] Compared with conventional traditional Chinese medicine formulations, microsphere-based TCM preparations can maintain higher drug concentrations at the target organ or in the bloodstream, offer more diverse routes of administration, provide prolonged therapeutic efficacy, and exhibit a high safety profile. Targeted microspheres typically use biodegradable materials as carriers, which can reduce adverse drug reactions, demonstrate excellent biocompatibility, enhance drug targeting, and mask unpleasant taste profiles. These formulations are now widely used in embolization therapy for hepatocellular carcinoma and other malignant tumors. ^[6] . Cantharidin is the active constituent in blister beetles that exhibits antitumor activity; however, it has a strong irritant effect on the urinary system and is therefore poorly tolerated by patients. Wang Guangsheng ^[7] For the first time, its bis-demethylated analogue, norcantharidin, was synthesized, effectively addressing this issue; it has now been used clinically for many years with good therapeutic efficacy. However, norcantharidin is unstable in vivo and, at slightly higher doses, is prone to adverse reactions. To enhance the targeting and safety of norcantharidin formulations, many researchers have turned their attention to novel drug-delivery materials to improve targeted administration. Ma et al. ^[8] Norcantharidin-loaded lipid microspheres were prepared using the concentrated homogenization method and the phospholipid complex method, achieving a drug encapsulation efficiency of over 80%. The stability of the formulation was significantly enhanced, with markedly increased drug distribution in the liver, spleen, and lungs, while drug distribution in the kidneys was slightly reduced. These findings indicate that the use of lipid microspheres can improve targeting and reduce nephrotoxicity. Song Yuling ^[9] Chitosan-based microspheres loaded with norcantharidin were prepared via an emulsion–chemical cross-linking method and evaluated for hepatic arterial embolization therapy. The results demonstrated that, during the observation period, the tumor volume and growth curve of VX2 hepatocellular carcinoma in the treated rabbits were significantly suppressed, indicating that the norcantharidin-loaded chitosan microspheres for hepatic arterial embolization exert a certain therapeutic effect on VX2 hepatocellular carcinoma in rabbits. Moreover, these microspheres reduced drug-related adverse effects, prolonged the drug-release duration, and decreased the frequency of administration.

1.2 Liposome

Liposomes are囊状小球 composed of one or more layers of lipid bilayers, with a structure similar to biological membranes. As drug-delivery carriers for traditional Chinese medicines, they can encapsulate drugs with varying polarities, carry substantial amounts of medication, and offer advantages such as enhanced therapeutic efficacy, improved drug stability, and reduced toxicity. In vivo, liposomes can be taken up by macrophages and accumulate in tissues rich in mononuclear phagocytes, such as the bone marrow, liver, and spleen, thereby exerting targeted effects. The particle size, surface charge, number of lipid layers, lipid composition, and surface modifications with polymers and ligands all influence the stability of liposomes both in vitro and in vivo. A layer of… ^[10] Compound liposomes were modified with the angiopep peptide to prepare compound shuyu-jian nao brain-targeted liposomes. These liposomes can cross the blood–brain barrier, and compared with conventional liposomes, they exhibit a markedly higher drug concentration in the rat brain, demonstrating excellent brain-targeting properties. Quercetin is a natural flavonoid that, in addition to its antioxidant activity, also displays potent pro-apoptotic effects on tumor cells, thereby inhibiting tumor cell growth at various stages of the cell cycle. However, its clinical application is limited by poor oral bioavailability and low water solubility. Encapsulation within liposomes, on the other hand, improves quercetin’s targeting ability, safety, biocompatibility, biodegradability, and toxicity profile. ^[11] This indicates that the quercetin-loaded liposomal drug delivery system holds great promise for use as an anticancer chemotherapeutic agent. Despite the numerous advantages of liposomes, several limitations remain: the tumor microenvironment is highly complex, and single-agent therapies often fail to achieve satisfactory therapeutic outcomes; cholesterol, an essential component in liposome formulation, has come under scrutiny due to religious and vegetarian concerns; furthermore, studies have shown that cholesterol in liposomes can modulate serum lipoprotein levels, potentially triggering “complement-mediated pseudoallergic reactions” in some patients, which may lead to pulmonary arterial hypertension and other adverse effects. ^[12] , which undoubtedly casts a shadow over the application of liposomes. To address the aforementioned drawbacks, Hong et al. ^[13] A ginsenoside Rh-based approach has been developed. ₂ the multifunctional liposome system (Rh ₂ -Lipo), innovatively challenges the conventional role of cholesterol as a liposome component. Unlike traditional liposomes, Rh ₂ -Both cholesterol and PEG in Lipo are bound by ginsenoside Rh. ₂ Replace with ginsenoside Rh ₂ It simultaneously functions as a membrane stabilizer, a long-circulating stealth agent, an active targeting ligand, and a chemotherapeutic adjuvant, making it a multifunctional carrier—truly “killing four birds with one stone.” In the 4T1 breast cancer xenograft tumor model, paclitaxel Rh ₂ - Liposomes demonstrated highly effective inhibition of tumor growth. Rh ₂ -Lipo offers a novel and promising research direction for drug-delivery systems targeting anticancer agents, holding the potential to address the limitations of liposomes.

1.3 Nanoparticle

Nanoparticles are solid colloidal particles composed of natural or synthetic polymeric materials, with diameters ranging from 10 to 500 nm. They exhibit high encapsulation efficiency, excellent stability, and biodegradability. Following intravenous administration, they are typically taken up by mononuclear phagocytes and predominantly accumulate in the liver, spleen, and lungs. Compared with liposomes, nanoparticles demonstrate superior targeting capabilities, leading to the increasing clinical application of nanoparticle-based formulations. ^[14] Curcumin is a polyphenolic compound extracted from turmeric, exhibiting a wide range of pharmacological activities, including anti-inflammatory, antibacterial, antiviral, and antitumor effects. ^[15-16] In practical applications, it has been found that curcumin exhibits low solubility, poor stability, and low bioavailability, which significantly limits its therapeutic potential. Rachmawati et al. ^[17] Using dichloromethane as the solvent and vitamin E polyethylene glycol succinate as the surfactant, curcumin-loaded polylactic acid nanoparticles were prepared via an emulsification–solvent evaporation method, followed by process optimization to obtain a polymeric nanocarrier with optimal performance, thereby providing a reference for the development of curcumin-based nanomedicines. Hong Feng et al. ^[18] Curcumin and a photothermal agent were loaded into a vascular endothelial growth factor (VEGF)-targeted mesoporous silica nanoparticle drug-delivery system, and the system’s tumor-cell-killing efficacy was evaluated. The results showed that this system enhances curcumin’s water solubility, in vivo stability, and cellular uptake; moreover, the combined use of curcumin and the photothermal agent exerts a synergistic effect, achieving up to 99% tumor-cell killing. In addition, this mesoporous silica nanoparticle drug-delivery system demonstrates excellent drug-loading capacity and can accommodate most therapeutic agents, offering a novel approach to address challenges such as poor in vivo stability, low solubility, and lack of targeting. Almutairi et al. ^[19] Curcumin-loaded fungal chitosan nanoparticles were prepared, and their therapeutic effects on human colon cancer HCT-116 cells and lung cancer A-549 cells were investigated. After 72 hours, most of the cancer cells entered the apoptotic phase; by 96 hours, the cell death rates in HCT-116 and A-549 cells had reached 67.6% and 73.8%, respectively. These results confirm that fungal chitosan nanoparticles can serve as a drug-delivery system for curcumin, enhance its anticancer activity against various human cancer cell lines, and promote both autophagy and apoptosis.

2 Active-targeting formulations

Active-targeting formulations involve surface modification of drug-loaded nanoparticles to prevent their uptake by macrophages and to inhibit their accumulation in the liver and spleen, thereby altering the natural biodistribution of the nanoparticles and enabling targeted delivery of the drug to specific target sites to exert therapeutic effects. Active-targeting formulations are mainly categorized into two types: surface-modified formulations and prodrug formulations. The former involves modifying the drug carrier to direct the drug to the target site for therapeutic action, while the latter entails converting the drug into a prodrug that is activated at the target site to exert its pharmacological effect.

2.1 Surface-modifying formulation

Based on the type of drug-delivery carrier, surface-modified formulations can be broadly classified into three major categories: modified liposomes, modified microspheres (or microcapsules), and modified nanoparticles, as shown in Figure 1.

In the 1990s, some scholars ^[20-21] It has been confirmed that a large number of glycyrrhetinic acid receptors are present on the surface of hepatocytes, endowing glycyrrhetinic acid with strong liver-targeting and hepatic distribution characteristics, thereby providing new insights for the development of active liver-targeted drug formulations. Mao Shengjun et al. ^[22] For the first time, glycyrrhetinic acid–surface-modified liposomes were successfully prepared, which can specifically bind to glycyrrhetinic acid receptors on the surface of hepatocytes, thereby laying the foundation for further research and development of an active-targeting drug delivery system for hepatocytes. On this basis, Wu Chao and colleagues ^[23] The glycyrrhetinic acid molecule was modified to synthesize glycyrrhetinic acid stearyl ester-3- O - Galactose-containing amphiphilic targeting molecules were used to modify norcantharidin-loaded liposomes. The resulting modified liposomes exhibited an encapsulation efficiency of 56.29% and a liver-targeting index of 5.213. Zhang Li et al. ^[24] Paclitaxel-loaded hyaluronic acid nanoparticles were modified with glycyrrhetinic acid, and their in vitro properties were evaluated. The drug-loading capacity and encapsulation efficiency were both satisfactory. The MTT assay demonstrated that these nanoparticles exerted cytotoxic effects on multiple tumor cell lines, while cellular uptake experiments indicated that they are readily taken up by tumor cells, thereby enhancing drug accumulation at the tumor site and improving therapeutic efficacy—providing a reference for their clinical application. Curcumol is the principal anticancer active constituent of Curcuma zedoaria; however, its poor water solubility has hindered its clinical use. Liposomes containing curcumol have been reported in the literature, but all such formulations are passive-targeting systems. Li et al. ^[25] For the first time, curcumol was encapsulated in a galactosylated liposomal matrix, thereby preparing galactosylated curcumol liposomes. The galactose moieties on the liposome surface can specifically bind to asialoglycoprotein receptors on the surface of hepatocytes, making this formulation an active liver-targeting delivery system. The research group optimized the preparation process and found that a two-step method significantly improved the encapsulation efficiency, particle size, and stability of the liposomes, providing a valuable reference for the development of liver-targeted curcumol formulations. Hasanpoor et al. ^[26] Human serum albumin–curcumin nanoparticles were functionalized with protein programmed death ligand 1 (PDL1) to enhance their targeting specificity toward breast cancer cells. Cell viability and apoptosis assays demonstrated that PDL1-modified human serum albumin–curcumin nanoparticles exhibited greater cytotoxicity against breast cancer cells than free curcumin, while also showing improved drug uptake. These findings suggest that PDL1 holds promise as a target for selective drug delivery and could be exploited in the treatment of PDL1-expressing breast cancers. Zhang Huidi ^[27] Modifying liposomes with VEGF antibodies and encapsulating paeonol within them can increase the drug’s retention in the dermal layer and block the biological effects of VEGF. A study was conducted to evaluate the skin irritation and therapeutic efficacy of a transdermal formulation consisting of paeonol-loaded, VEGF antibody-modified liposomes. The results showed that the formulation exhibited no irritant effect on rabbit skin and effectively treated hypertrophic scars on the ears of rabbits. Xingnaojing injection is derived from the classic prescription “Angong Niuhuang Wan”; however, it is inconvenient to administer, has a high incidence of adverse reactions, and enters the brain relatively slowly. To address these shortcomings, Wen Ran ^[28] mPEG was prepared for Xingnaojing. ₂₀₀₀ -PLA copolymer-modified microemulsions, administered via the nasal route, enhance the brain-targeting efficacy of the drug. Moreover, after modification, the microemulsions exhibit markedly reduced irritancy to the nasal mucosa, thereby demonstrating high clinical applicability.

2.2 Prodrug formulation

Prodrugs are compounds obtained by chemically modifying a pharmacologically active parent drug; they exhibit little or no activity in vitro but release the parent drug upon biotransformation in vivo, thereby exerting therapeutic effects. The application of prodrugs in the field of anticancer drugs has attracted considerable attention, and the low bioavailability of curcumin has long been a major obstacle to its clinical use, prompting extensive research aimed at overcoming this challenge. Ozawa-Umeta et al. ^[29] A water-soluble, injectable curcumin β- has been synthesized. D -Glucuronic acid, used in the treatment of colorectal cancer, is converted in vivo into the free form of curcumin via β-glucuronidase following intravenous administration. The plasma levels of the curcumin prodrug are more than 1,000 times higher than those achieved with conventional oral administration, resulting in a significant improvement in bioavailability. Immunohistochemical analysis revealed a marked reduction in nuclear factor κB activity in the tumor tissues of mice in the treatment group, and no free curcumin was detected in organs outside the target site. These results indicate that curcumin β- D -Glucuronic acid exhibits low toxicity and is a promising therapeutic agent for colorectal cancer. Nasrollahi et al. ^[30] It was reported that maltogenic α-amylase (Maase, EC 3.2.1.133) exhibits strong selectivity for cyclodextrins and can rapidly hydrolyze them, with the drug expected to be released upon the hydrolytic ring-opening of β-cyclodextrin (β-CD). Subsequently, this research group developed a novel targeted controlled-release drug delivery system based on an antibody–enzyme prodrug approach. ^[31] This system comprises two components: a prodrug based on a β-cyclodextrin–curcumin inclusion complex and an enzyme–antibody conjugate derived from a Maase–trastuzumab complex. Immunocytochemical analysis demonstrated that the prodrug complex exhibits high degradation activity toward β-cyclodextrin and displays significant binding affinity for human epidermal growth factor receptor-2-positive tumor cells, facilitating rapid release of curcumin at the cell surface and thereby achieving encapsulation and controlled release of the compound.

3 Physicochemical Targeted Formulations

Physicochemical-targeted formulations are targeted drug-delivery systems that employ specific physicochemical approaches to ensure drug efficacy at designated sites, such as magnetic, thermal, or pH-responsive targeting.

3.1 Magnetic Targeting Formulation

Magnetic targeted formulations belong to the fourth generation of targeted drug delivery systems, consisting of magnetic composite drug carriers and polymeric matrices. Under the influence of an external magnetic field, these formulations enable the concentrated accumulation and controlled release of the drug at the target site, thereby achieving targeted therapy. Compared with other targeted delivery systems, magnetic targeted formulations offer advantages such as superior targeting specificity, high drug-loading capacity, and reduced uptake by the reticuloendothelial system. ^[32] , research in this area is highly active, with therapeutic effects on various solid tumors, including those of the liver and stomach. Both domestically and internationally, extensive studies have been conducted on paclitaxel and other individual components of traditional Chinese medicines, as shown in Table 1. In addition, Lin et al. ^[40] Paclitaxel–epidermal growth factor receptor peptide–conjugated magnetic polymer liposomes were prepared, and in vivo liver-targeting studies in nude mice demonstrated that, under the influence of a magnetic field, this complex accumulates in the liver. Furthermore, driven by the targeting effect of the epidermal growth factor receptor, it also diffuses into tumor cells, suggesting that this formulation holds promise as an effective drug-delivery system for targeted therapy of hepatocellular carcinoma. To address the issue of poor local localization of paclitaxel, which often leads to systemic adverse reactions, Feng et al. ^[41] A novel poly(lactic-co-glycolic acid) (PLGA) magnetic Janus particle (DMJP) drug-delivery system has been developed, comprising three distinct functional compartments: paclitaxel for cytotoxicity against cancer cells, magnetite (Fe ₃ O ₄ ) Nanoparticles are used for targeted delivery, and rhodamine B serves as a fluorescent tracer to provide real-time visualization of the interaction between DMJPs and cancer cells. Under an external magnetic field, DMJPs are guided to accumulate specifically at the target cell site and subsequently enter the cells. Moreover, DMJPs exhibit specific and high cytotoxicity only against human breast cancer MDA-MB-231 cells, with no significant toxicity observed in mouse embryonic fibroblast NIH-3T3 cells. The specific targeting of DMJPs toward cancer cells will greatly minimize potential adverse effects, holding promise for the development of novel precision drug-delivery systems for malignant tumors. Emodin is one of the major constituents of rhubarb and has been shown to inhibit tumor growth and metastasis. However, its clinical application is primarily limited by poor targeting efficiency and low solubility, as reported by Song et al. ^[42] Emodin was loaded into the lipid bilayer of liposomes, while high-performance magnetic iron oxide nanoparticles were encapsulated within a hydrophilic bilayer. The resulting emodin-loaded magnetic liposomal nanoparticles exhibited a 24.1% higher cytotoxicity against human breast cancer MCF7 cells at a low concentration (16 μg/mL) compared with free hydrophobic emodin. Moreover, upon application of an external magnetic field, these magnetic liposomes accumulated efficiently in vivo in mice, which helps reduce the therapeutic dose of emodin. These findings suggest that emodin-loaded magnetic liposomes represent a novel sub-targeting formulation for the treatment of malignant tumors.

3.2 Thermo-sensitive targeted formulation

Thermo-sensitive liposomes, also known as temperature-responsive liposomes, have emerged as a major focus in tumor-targeted therapy in recent years. These nanoscale liposomes can selectively accumulate at the tumor site: at normal body temperature, their lipid bilayers are orderly and densely packed, encapsulating the therapeutic payload within; however, upon reaching a pre-heated target site, the liposome membrane undergoes a phase transition due to the elevated temperature, increasing its permeability and dramatically enhancing the mobility of the encapsulated drug, which then diffuses into the target tissue and achieves a high local drug concentration, thereby realizing the goal of targeted therapy. ^[43] According to some literature, cancer cells are more sensitive to high temperatures than healthy cells, with their phase-transition temperature typically exceeding normal body temperature; therefore, cancer cells are more easily killed. ^[44] ; Meanwhile, numerous studies have already demonstrated that hyperthermia can also enhance the cytotoxicity of certain chemotherapeutic agents. ^[45] , to enhance the therapeutic effect. Li Chenglong ^[46] Temperature-sensitive paclitaxel liposomes were prepared using the thin-film hydration method, exhibiting a high encapsulation efficiency, favorable biological properties, and controlled drug release. Hao et al. ^[47] Peptide iRGD-modified conjugated linoleic acid–paclitaxel nanoliposomes were prepared, and their effects on B16-F10 melanoma cells were investigated. Both in vitro and in vivo antitumor activities demonstrated that these liposomes exhibit thermosensitivity at 42°C, with high cellular uptake, thereby inhibiting tumor growth and prolonging survival. Thermosensitive liposomes combine the dual advantages of liposomes and hyperthermia, further enhancing drug targeting.

Multifunctional therapeutic systems have emerged as a major frontier in medical research in recent years, and drug-delivery systems combining thermosensitive liposomes with magnetic-targeting formulations have opened up new avenues for the application of targeted delivery. Magnetic-targeted thermosensitive liposomes can, under the influence of an external magnetic field, accumulate at the target site via systemic circulation; the conversion of magnetic energy into heat elevates the temperature at the target site, triggering drug release and thereby enhancing the targeting efficiency of the therapeutic agent. Ribeiro et al. ^[48] Gemcitabine–paclitaxel thermosensitive magnetic liposomes were prepared, and their release profiles and cytotoxic effects on breast cancer MCF-7 cells were investigated. The results demonstrated that these liposomes exhibit favorable tumor-targeting accumulation; at the phase-transition temperature, the release rates of gemcitabine and paclitaxel increased by 85% and 42%, respectively, compared with physiological temperature. Moreover, compared with hyperthermia alone (50%) or chemotherapy alone (40%), the combination of magnetic liposome delivery and hyperthermia (73%) more effectively reduced cancer cell viability, suggesting that gemcitabine–paclitaxel liposomes hold great potential for cancer therapy. Zheng et al. ^[49] Nanometer-sized coix seed oil thermosensitive magnetic liposomes were prepared, exhibiting excellent magnetic targeting and rapid drug-release properties, with a phase-transition temperature of approximately 42°C. Upon application of an external magnetic field and subsequent heat treatment, the inhibitory effect on human hepatocellular carcinoma HepG2 cells was significantly enhanced, demonstrating the advantages of thermosensitive magnetic liposomes in the field of cancer therapy. Deng et al. ^[50] Paclitaxel-loaded near-infrared–responsive multifunctional liposomes were prepared, exhibiting excellent near-infrared optical properties, magnetic responsiveness, and temperature sensitivity. Near-infrared fluorescence imaging was employed to track the interactions between cancer cells and the drug, while thermal treatment and alternating magnetic field exposure significantly enhanced the anticancer efficacy of the formulation (Figure 2), demonstrating substantial potential for both cancer diagnosis and therapy.

3.3 pH Sensitive Targeted Formulation

pH-sensitive drug-delivery systems typically incorporate pH-responsive components, such as weakly acidic functional groups or acid-labile chemical bonds, which ensure stability under physiological pH conditions (pH 7.4) but destabilize in mildly acidic environments, leading to increased membrane permeability and subsequent drug release. ^[51] . In contrast, the pH of tumor tissues is typically between 5.0 and 5.6. ^[52] , which enables rapid drug release at the targeted site to exert therapeutic efficacy. Calcium phosphate is pH-sensitive and can increase drug concentration at the tumor site; based on this, Ru et al. ^[53] pH-sensitive triptolide-loaded calcium phosphate liposome nanoparticles were prepared, and their stability, pH sensitivity, and cytotoxic effect on ovarian cancer SKOV-3 cells were experimentally confirmed. Compared with free triptolide, these nanoparticles exhibit significantly reduced toxicity to the female reproductive system, suggesting they could serve as a novel approach for chemotherapy of ovarian cancer. Folate receptors are expressed at levels two orders of magnitude higher in malignant tumor cells than in normal cells, and folate and its drug conjugates display very high affinity for these receptors. ^[54] , and thus can serve as a target for anticancer drugs. Monteiro et al. ^[55] Paclitaxel–folic acid–coated long-circulating pH-sensitive liposomes were prepared, and the pH sensitivity of this system was confirmed through phase-transition changes in the structural lipids. At a pH of approximately 5.0, the system enhances drug concentration at the tumor site by increasing liposomal membrane permeability or facilitating fusion with endosomal membranes, thereby more effectively delivering paclitaxel into tumor cells, inhibiting tumor cell division, and augmenting in vivo antitumor efficacy. Liu Xiaofang et al. ^[56] Curcumin-sensitive liposomes were modified with folic acid–chitosan to yield folic acid–chitosan–curcumin-sensitive liposomes, which exhibit high encapsulation efficiency and excellent stability, enabling the drug to accumulate efficiently at the target site. In release media at pH 7.4 and 5.5, the 48-hour cumulative release rates demonstrated pronounced folic acid receptor–mediated targeting. In addition to pH-sensitive liposomes mediated by folic acid receptors, recent years have also seen numerous studies on pH-sensitive liposomes modified with other materials, such as the impact of polyethylene glycol coating on the biodistribution and tumor-targeting accumulation of pH-sensitive liposomes. ^[57] , The Effect of Hyaluronic Acid-Functionalized pH-Sensitive Liposomes on Gemcitabine Resistance ^[58] , Effect of Cationic Polylysine on the Release from pH-Sensitive Anionic Liposomes ^[59] and so on. Banxia Xiexin Tang is a classic formula recorded in the Treatise on Cold Damage Disorders, and it has demonstrated good therapeutic efficacy in clinical practice for conditions such as chronic gastritis, gastric ulcer, and functional dyspepsia. Yu Qiao et al. ^[60] Acrylic resin was selected as the coating material to prepare a Pinellia–Scutellaria–Glycyrrhiza pH-dependent colon-targeted tablet. The coating layer begins to dissolve at pH values greater than 7.0, thereby achieving colon-specific drug release; moreover, no drug release occurs in simulated gastric fluid. In phosphate buffer at pH 7.8–8, the drug release reaches over 85% within 1 hour, indicating that this formulation can effectively achieve colon-targeted drug delivery.

4 Summary and Outlook

With the gradual maturation of technologies for the extraction and separation of active constituents in traditional Chinese medicine (TCM) and the increasingly in-depth investigation of their pharmacological mechanisms, the development of new TCM formulation technologies and novel dosage forms has become a core component of TCM modernization. In the past, low solubility, poor stability, and limited targeting ability of TCM constituents constrained their clinical application; however, the integration of TCM with targeted delivery systems can address these challenges from multiple angles, making this an important direction for the advancement of modern TCM formulations with broad prospects. Current research indicates that the development of targeted formulations and other novel dosage forms has fundamentally transformed traditional TCM dosage forms and manufacturing processes, revitalizing conventional TCM through the support of modern technologies. Nevertheless, research on targeted formulations still faces several limitations: (1) many drugs are restricted in clinical use due to poor stability, particularly those intended for intravenous administration; (2) most studies on TCM-targeted formulations remain at the laboratory stage, with limited clinical application; (3) existing research predominantly focuses on individual TCM compounds rather than on active fractions or complex TCM formulas; and (4) some targeted formulations have relatively low drug-loading capacities; therefore, increasing drug loading while reducing dosing frequency would be highly beneficial in minimizing drug-related toxicities and adverse effects.

Traditional Chinese medicine (TCM) compound formulations possess significant clinical advantages and practical value; however, most TCM-targeted formulations studied to date are based on single TCM constituents. This is primarily due to the large number of herbal ingredients and complex compositional profiles in TCM compound formulas, which pose substantial challenges for in vivo pharmacokinetic research. Some scholars contend that the in vivo pharmacokinetic studies of one or more known active constituents are quite similar to those of synthetic drugs, as both rely on instrumental methods to determine the plasma concentrations of the active components. The material basis for multi-target actions lies in the active constituents found in both single herbs and TCM compound formulas, and this can be leveraged when developing targeted formulations derived from TCM compound preparations. ^[1] Research on targeted formulations of traditional Chinese medicine (TCM) compound prescriptions can initially focus on those with a limited number of herbal ingredients, well-defined active constituents, pronounced therapeutic effects, and controllable quality. In the future, the application of TCM-targeted formulations must be grounded in the fundamental theories of TCM, with intensified studies on the pharmacodynamics and pharmacokinetics of TCM’s active components. Emphasis should be placed on the development of TCM compound formulations, while also exploring novel drug-delivery materials, in order to achieve further progress.

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