Nanomedicine for Oral Chemotherapy

Keywords::

• bioavailability
• biodegradable polymers
• cancer nanotechnology
• chemotherapeutic engineering
• docetaxel
• gastrointestinal barrier

Oral chemotherapy is one of the most important issues in 21st century medicine. It may radically change the current regimen of chemotherapy, as well as greatly improve the quality of life of patients. In comparison with the current practice of chemotherapy (i.e., intravenous injection or infusion), which causes high peak above the maximum tolerable drug concentration in the plasma and fast excretion of the drug from the circulatory system, oral chemotherapy can maintain a sustained and mild drug concentration in the circulation to achieve a prolonged exposure of cancerous cells to the drug. This will increase the therapeutic efficacy and decrease the side effects. Moreover, oral chemotherapy is an important step to realize the patients’ dream of ‘chemotherapy at home‘, which will greatly improve their quality of life and give hope to those with late-stage cancer, who have been too weak to tolerate any treatment in the current clinical regimen. Oral chemotherapy provides at least a palliative treatment to give them hope and extend their life [1]. Unfortunately, most anticancer drugs, especially those with excellent anticancer effects such as taxanes (paclitaxel and docetaxel), are not orally bioavailable (i.e., not absorbable/interactive in the GI tract). For paclitaxel, for example, the initial studies reported that its oral bioavailability was less than 1% [2]. As we know, our body is so perfectly structured that all important organs are protected from external toxins by the so-called physiological drug barriers, such as the blood–brain barrier and the gastrointestinal (GI) barrier. The molecular basis of the various physiological drug barriers had been unknown until the past decade when understanding of the molecular biology has made significant progress. For oral bioavailability of taxanes, which are the number one seller among the various anticancer drugs and had US$3.6 billion annual sale in 2006 in the world market, an intensive investigation across the new millennium has been achieved, which shows that orally administrated drugs, such as paclitaxel, would be eliminated from the first-pass extraction by the cytochrome P450-dependent metabolic processes and the overexpression of plasma membrane transporter P-glycoprotein (P-gp) in the involved physiological systems, especially the intestines, liver and kidneys. Excellent work using wild-type and P-gp knockout mice has demonstrated the role of P-gp in multidrug resistance and bioavailability of paclitaxel and other anticancer drugs. Measurements of paclitaxel concentration in the plasma after oral administration showed that the area-under-the-curve (AUC) of the drug concentration in the plasma versus time was sixfold higher in the P-gp knockout mice than in the wild-type mice. After intravenous administration of paclitaxel, the AUC was only twofold higher in the P-gp knockout mice compared with the wild-type [3].

Possible solutions for oral delivery of paclitaxel, docetaxel and other anticancer drugs have been under intensive investigation. The general idea is to apply P-gp/P450 inhibitors, such as cyclosporine A (for paclitaxel) and ritonavir (for docetaxel), to suppress the elimination process [4–7]. However, P-gp/P450 inhibitors also suppress the body‘s immune system and thus cause medical complications. Moreover, P-gp/P450 inhibitors may have their own side effects and problems in formulation for clinical administration. The development of specific, low-toxicity inhibitors and other drug-metabolizing enzymes, such as dihydropyrimidine dehydrogenase would represent a major advance in the successful formulation of oral chemotherapy [8].

Nanomedicine has been defined as the application and further development of nanotechnology to solve problems in medicine (i.e., to diagnose, treat and prevent diseases at the cellular and molecular level). Nanomedicine may radically change the way we make drugs and the way we take drugs, and thus provide an ideal solution for oral chemotherapy [9,10]. Typical examples are application of the various nanocarriers, such as conjugated chitosan, micelles, liposomes, solid lipid nanoparticles (NPs) and NPs of biodegradable polymers, for controlled, sustained and targeted drug delivery across the various physiological drug barriers, including the GI barrier for oral chemotherapy and the blood–brain barrier for treatment of CNS diseases. It has been shown, for example, that paclitaxel formulated in D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS or simply TPGS) emulsified poly(lactic-co-glycolic acid) (PLGA) NPs could realize a 168 h sustained chemotherapy in comparison with 22 h for Taxol^® in the same 10 mg/kg dose and 400% maximum tolerance dose for rats [11]. The feasibility of nanomedicine was then further confirmed by the NPs of poly(lactide)/vitamin E TPGS (PLA-TPGS) copolymer for controlled and sustained delivery of paclitaxel and docetaxel. It has been found that paclitaxel formulated in the PLA-TPGS NPs could realize a 240 h sustained chemotherapy with 1.6-fold AUC (a quantitative index for the in vivo therapeutic effect) compared with Taxol [12] and that docetaxel formulated in PLA-TPGS NPs could realize a 336 h sustained chemotherapy with 3.4-fold AUC compared with Taxotere^®[13]. Biodistribution of the formulated drug could also be enhanced with more in lung and some in brain. This inspired research could help to develop drug-delivery systems of biodegradable NPs of small enough size and appropriate surface modification to improve the adhesion and absorption of the NPs to transport the drug across the GI barrier, thus realizing a method of oral chemotherapy. Although there have been a few preliminary reports, the results obtained were far from comparable to intravenous administration [14,15].

Biodegradable polymers are the material basis of nanomedicine products for oral chemotherapy. Adjuvant technology has been most often used in the pharmaceutical industry to develop dosage forms of potent drugs that have problems in solubility, permeability and stability. Adjuvant is a pharmacological or immunological agent that is used to formulate drugs and vaccines for clinical administration while having little if any direct effects when given by itself. Biodegradable polymers can be seen as a special type of adjuvant for drug formulations, which carries the drug, improves its pharmaceutical properties and enhances its adsorption, distribution, metabolism and excretion process, thus strongly influencing pharmacokinetics and pharmacodynamics of the drug. They are biodegradable (i.e., decomposed from macromolecules to small molecules) and, thus, can be easily removed from the body after completion of their task as a drug carrier. Various US FDA-approved biodegradable polymers are commercially available. Those used most often in the research of nanomedicine include PLA, PLGA and poly(ε-caprolactone), for example. It seems, however, that most of them could not achieve the desired effects in the development of nanomedicine products since they were originally synthesized mainly for textile grafts and implants in the 1950s, rather than for drug-delivery purposes. They are highly hydrophobic and thus not friendly to hydrophilic drugs. They have too great mechanical strength and their degradation is too slow, resulting in insufficiently quick drug release to meet therapeutic needs. The bioactivity of the encapsulated agents may also deteriorate. Moreover, NPs made up of those polymers are difficult to directly conjugate to hydrophilic molecular probes for targeting, for which amphiphilic linker molecules are needed, causing complications in targeting technology. Since it usually takes more than 10 years to develop a new biodegradable polymer and have it approved for clinical use, two strategies have been developed to solve this problem [9]: one is to coat the NPs with hydrophilic polymers, for which a good example is the TPGS-emulsified PLGA NPs [11]; and the other is to synthesize copolymers to insert hydrophilic elements in the hydrophobic chains of the polymers, for which a good example is the PLA-TPGS NPs [12,13].

A typical example of oral chemotherapy by surface-modified NPs of US FDA-approved biodegradable polymers is the TPGS-emulsified PLGA NP for oral delivery of paclitaxel [14]. TPGS is a PEGylated vitamin E, which has been found to be able to enhance cellular uptake and circulating time of the coated NPs. Moreover, TPGS can achieve much higher emulsification effects than other emulsifiers such as poly(vinyl alcohol). The TPGS-emulsified PLGA NPs formulation of paclitaxel was found to have great advantages over Taxol. The in vitro viability experiment showed that such a NP formulation could be 1.28, 1.38 and 1.12-times more effective than Taxol after 24, 48 and 72 h incubation with MCF-7 human breast cancer cell line at 2.5 µg/ml paclitaxel concentration, respectively. In vivo evaluation confirmed the advantages of the TPGS-emulsified PLGA NP formulation versus Taxol in promoting oral bioavailability of paclitaxel. Such a NP formulation achieved more than ten-times higher oral bioavailability than Taxol, which resulted in a 9.74-fold greater therapeutic effect and a 12.56-fold longer sustainable therapeutic time than Taxol. In short, the bioavailability of a TPGS-emulsified PLGA NP formulation of paclitaxel is 24.0%, much higher than that of the medical solution (i.e., coadministration of cyclosporine A).

As for oral drug delivery by NPs of biodegradable copolymers, a good example can be found from the system of biodegradable poly(d,l-lactide-co-glycolide) NPs incorporated with a medical clay, montmorillonite (PLGA/MMT NPs) for oral chemotherapy by using paclitaxel as a prototype drug [15]. MMT could adsorb dietary, bacterial and metabolic toxins associated with GI disturbance, resulting in a host of common symptoms, such as nausea, vomiting and diarrhea, most of which are typical side effects caused by anticancer drugs. The PLGA/MMT NP formulation of paclitaxel thus represents a new concept in developing drug delivery systems, formulating the drug carrier from a material that can also have therapeutic effects, either synergistic with, or capable of mediating the side effects of the encapsulated drug. It was found that MMT could enhance cellular uptake efficiency of pure PLGA NPs by 57–177% for Caco-2 cells, which were used as an in vitro model of the GI barrier and 11–55% for HT-29 cells that were used as model cancer cells, depending on the amount of MMT in the NPs and the particle concentration in incubation. Unfortunately, in vivo PK was not carried out. The bioavailability of that formulation is thus unknown.

In a recent publication, Feng et al. carried out a systematic investigation of oral drug delivery by NPs of biodegradable polymers. They developed four NPs of biodegradable polymers for oral delivery of anticancer drugs, with docetaxel used as a model drug: PLGA NPs, PLA-TPGS NPs, PLGA/MMT NPs and PLA-TPGS/MMT NPs [16]. The design aimed to take advantage of TPGS and/or MMT in NP technology for drug delivery. The drug-loaded NPs were prepared by a modified solvent extraction/evaporation method. Cellular uptake of the corresponding coumarin 6-loaded NPs was investigated. In vitro cancer cell viability experiments showed that judged by IC₅₀, the PLA-TPGS/MMT NP formulation was 2.89, 3.98 and 2.12-fold more effective and the PLA-TPGS NP formulation was 1.774, 2.58 and 1.58-fold more effective than Taxotere after 24, 48 and 72 h treatment, respectively. In vivo PK experiment with SD rats showed that oral administration of the PLA-TPGS/MMT NP formulation and the PLA-TPGS NP formulation could achieve 26.4- and 20.6-times longer half-life, respectively, than intravenous administration of Taxotere at the same 10 mg/kg dose. One oral administration of the NP formulations could realize almost 3 weeks of sustained chemotherapy in comparison with 22 h of intravenous administration of Taxotere. The oral bioavailability can be enhanced from 3.59% for Taxotere to 78.0% for the PLA-TPGS/MMT NP formulation and 91.3% for the PLA-TPGS NP formulation, respectively. In short, the oral delivery of docetaxel by PLA-TPGS NP formulation can be made comparable with intravenous injection/infusion. Moreover, more desired pharmacokinetics and biodistribution can be achieved for better therapeutic effect and less side effects. It can be predicted that nanomedicine products for oral chemotherapy will soon appear on the market with great commercial success.

Financial & competing interests disclosure

This work is supported by the 7th Singapore–China Cooperative Research Project Call between Agency of Science, Technology and Research (A*STAR), Singapore and The Ministry of Science and Technology (MOST), China (PI: Si-Shen Feng, Singapore, and Jintian Tang, China). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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Funding

This work is supported by the 7th Singapore–China Cooperative Research Project Call between Agency of Science, Technology and Research (A*STAR), Singapore and The Ministry of Science and Technology (MOST), China (PI: Si-Shen Feng, Singapore, and Jintian Tang, China). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.