Liposomes as Drug Delivery Systems for the Treatment of TB

Marina Pinheiro; Marlene Lúcio; José LFC Lima; Salette Reis

Disclosures

Nanomedicine. 2011;6(8):1413-1428.

Classical TB Therapy

Clinical management of TB poses several serious questions (Figure 2).

(Enlarge Image)

Figure 2.

The clinical problems associated with TB chemotherapy.

The first obstacle is due to the reduction of the efficacy of chemotherapy. This may be attributed to degradation of the drug before reaching the target, the low levels of cell permeability to drugs or primary drug resistance. Other reasons for the failure of chemotherapy may be the difficulty in achieving adequately high drug concentrations at the infection site, inadequate penetration into macrophages, as well as inadequate penetration into the granulomas, which are as stated, reservoirs of latent bacteria in the host alveolar tissue.^[13,24] The treatment of mycobacterial infections is also difficult because, as mentioned, mycobacteria are highly resistant intracellular pathogens.^[26]

The TB treatment requires a long period of chemotherapy (6–9 months) with combinations of agents to minimize the emergence of antimicrobial resistance.^[24,27] The necessity of an extended period of treatment is a direct result of the lifecycle of the bacilli, some of which may enter into a 'latent' or 'persistent' phase after the initial infections.^[28] Hence, the long period of chemotherapy is first to destroy the population of actively multiplying bacilli that can be found initially, and secondly, to prevent reactivation of any latent bacillus present in granulomas that attempts to multiply. Finally, an option that is not usually considered is that the macrophages themselves, following their normal dynamics, drain the bacilli from granulomas towards the outside. Thus, by reducing inflammation and preventing multiplication of the bacilli, antibiotic treatment is also highly recommendable to prevent the continuous formation of FMs and their accumulation or movement through the alveolar spaces.^[29]

The most effective pharmacotherapy in TB treatment is a multidrug combination of isoniazid, pyrazinamide and rifampicin. During the initial intensive stage (2 months), these three agents are administered together with ethambutol. The second phase (4 months) comprises exclusively rifampicin and isoniazid. These four drugs, together with streptomycin, make up the so-called first-line therapy. Other drugs (e.g., rifabutin, ethionamide, amikacin, kanamycin A and levofloxacin) have been used in the treatment of TB; however, these are considered as a second-line therapy since these are more toxic, more expensive and less active than first-line agents.^[12]

Besides the abovementioned classical therapeutic regimes, new drugs with interest for TB treatment are being developed and they are presently in different steps of preclinical or clinical trials. This issue is out of the scope of this article, but additional information can be found in the following references.^[28,30–41]

Although the development of new anti-TB drugs is an obvious approach to fight TB, mechanisms to improve the efficacy of existing drugs can represent a faster strategy. The long and necessary treatment schedules of classical chemotherapy are associated with severe toxic side effects, including hepatotoxicity, and result in poor compliance, one of the main reasons for the emergence of multidrug-resistant pathogens.^[15,42] In this regard, improvement of the therapeutic index of existing anti-TB drugs, namely by their encapsulation into nanodelivery systems, should be considered, aiming at maximization of the drug concentration at infected sites, reduction of toxic effects and reduction of treatment duration.^[15] Furthermore, the development of nanodelivery systems will provide an opportunity to exploit the inhalatory route, which will be of particular interest in the case of pediatric patients for which most of the first-line drugs are not available.^[12]

According to the mentioned disadvantages of classical chemotherapy and to the hope that has been put in a nanotherapeutic approach, this article will provide a state of art in the use of liposomes as nanodelivery systems for the treatment of TB.

1 2 3 4 5 6 7 8

Next Section

Cite this: Liposomes as Drug Delivery Systems for the Treatment of TB - Medscape - Oct 01, 2011.

Table 1. Liposomes for anti-TB delivery.
Drug(s)	Liposome type and composition	Type of targeting	Animal model (route of administration)	Therapeutic effect and toxicity	Conclusion	Ref.
Rifabutin	MLVs PC/DPPG	Passive	Mice (intravenously)	Significant reduction of bacilli present at the spleen and liver compared with the free drug group; no significant differences were observed in the lungs	Good approach for extrapulmonary TB. Could be a good approach for pulmonary TB through inhalatory administration	[15]
Amikacin	SUVs PC/Chol/DSPG	Passive	Mice (intravenously)	Increased activity against Mycobacterium tuberculosis and improved half-life of the drug encapsulated liposomes compared with the free drug ones	Reduction in frequency of administration	[74]
Pyrazinamide	MLVs DPPC/Chol	Passive	Mice (intravenously)	Increased efficiency compared with free drug: increased reduction in M. tuberculosis bacilli in the lungs; more effective histopathological examination	High therapeutic efficacy of pyrazinamide liposomes	[72]
Rifampicin and Isoniazid	MLVs PC/Chol	Passive	Guinea pigs (inhalatory)	Increased therapeutic drug levels in plasma with a single dose; drugs are present in the lungs and AMs	Reduction in frequency of administration	[75]
Rifampicin and Isoniazid	MLVs PC/Chol/O-SAP/DCP/DSPC-PEG 2000	Active (O-SAP, PEG and DCP)	Mice (intravenously)	Superior efficacy of the formulation: increased reduction of the liver, kidneys and lungs CFUs and normal lung weight; hepatotoxicity reduction and normal lung morphology, compared with the free drugs	Less toxic and more effective formulation than the free drugs	[13,66]
Rifampicin and Isoniazid	MLVs PC/Chol/DCP/DSPE-PEG 2000 and O-SAP	Active (O-SAP, PEG and DCP)	Mice (intravenously)	Superior efficacy of the formulation: reduction of the bacilli at the lungs, liver and spleen; no toxic effects found at the liver; maintenance of bilirubin, serum alanine transaminase and alkaline phosphatase levels	More effective and nonhepatotoxic formulation than the free drugs	[78]
Rifampicin	MLVs PC/Chol and O-SAP, MBSA or DCP	Active (O-SAP, MBSA or DCP)	Rats (inhalatory)	Formulations that carry ligands (O-SAP, MBSA) or DCP showed a preferential lung accumulation	The inhalatory route is liable in pulmonary TB having the AM as a target	[19]
Rifampicin	SUVs PC and tuftsin	Active (tuftsin)	Mice (intravenously)	Increased efficiency compared to free drug and control formulation without tuftsin: lung bacillus load and lung weight were significantly reduced	More effective formulation than the free drug and liposomes loaded with rifampicin	[60]
Not shown	MLVs Man-LIPO	Active (mannose)	Rats (inhalatory)	More efficiently delivered to AMs after pulmonary aerosolization; the formulation did not harm lung tissues	Man-LIPO are useful for efficient aerosolized liposomal delivery to AMs	[79]
Not shown	LUVs Man-LIPO	Active (mannose)	Rats (intratracheally)	Significantly high internalization and selective targeting to AMs in vivo for the liposomes with higher percentage of mannose	Efficient targeting to AMs	[80]
Rifampicin	MLVs DSPC/Chol	Not shown	In vitro (A549 cells)	Inferior toxicity compared with the free drug	Less toxic formulation to alveolar epithelial cell line comparing to the free drug	[81]
Amikacin	MLVs PC/DCP/Chol	Not shown	Not shown	Not shown	The negatively charged MLVs exhibited efficacy for amikacin encapsulation	[82]

AM: Alveolar macrophage; CFU: Colony-forming unit; Chol: Cholesterol; DCP: Dicetylphosphate; DPPC: Dipalmitoylphosphatidylcholine; DPPG: Dipalmitoylphosphatidylglycerol; DSPC: Distearoyloglycerophosphatidylcholine; DSPE: Distearoylphosphatidylethanolamine; DSPG: Distearoylphosphatidylglycerol; LUV: Large unilamellar vesicle; Man-LIPO: Mannosylated liposomes; MBSA: Maleylated bovine serum albumin; MLV: Multilamellar vesicle; O-SAP: O-steroyl amylopectin; PC: Phosphatidylcholine; PEG: Polyethylene glycol; SUV: Small unilamellar vesicle.

Executive Summary

TB Etiology, Physiopathology & Current Therapies

TB is the second most prevalent infectious disease after HIV, with which it is strongly associated. It accounts for a large number of worldwide deaths, but especially in developing countries.
Two of the major problems associated with TB, and which are closely related, are the lack of adherence to therapy and the emergence of multidrug-resistant strains to antibiotics.
No new anti-TB agents have been introduced in the market, thus it is urgent to improve the existent drugs to reduce the duration of treatment and promote adherence to therapy.

Liposome-based Drug Delivery Therapy

The use of liposomes as drug delivery systems increases protection against degradation of anti-TB drugs, allowing the coencapsulation of hydrophilic and hydrophobic drugs in the same formulation, as well as the increase in the therapeutic index of drugs. Furthermore, liposomes are biocompatible, which is of extreme importance concerning their use in clinical practice.

Routes of Administration That Can be Exploited in the Treatment of TB Having the Alveolar Macrophage as the Drug Target

The intravenous route using liposomes with anti-TB drugs is useful in the treatment of extrapulmonary TB. For the treatment of pulmonary TB using the same route of administration, it is necessary to add ligands to liposomes in order to enhance the selectivity for alveolar macrophages.
Inhalation is the most promising route for the treatment of TB. It is a noninvasive route and can be useful for both pulmonary TB and extrapulmonary TB.

Passive & Active Targeting of Liposomes Used in the Treatment of TB

The passive targeting is useful in pulmonary TB if the formulations are administered by inhalation. It is also interesting in extrapulmonary TB if the formulations are administered intravenously or by inhalation.
The active targeting improves the specificity and selectivity for the target in pulmonary TB. The addition of ligands to liposomes increases the concentration of drug that reaches the alveolar macrophage, where the etiologic agent of TB is housed. It may be a useful approach by inhalation and an essential approach by intravenous administration, as this allows a reduction in uptake by macrophages of the liver and spleen.

Liposomal Formulations With Immunostimulatory Activity

Therapeutic vaccines made of detoxified, fragmented Mycobacterium tuberculosis cells (e.g., RUTI) delivered in liposomes were developed to reduce the period of chemotherapy. The rationale of this therapy is first to take advantage of the bactericidal properties of chemotherapy to kill active growing bacilli, eliminate the outermost layer of foamy macrophages and reduce local inflammatory responses so as to avoid the predictable reaction phenomenon caused by M. tuberculosis antigens when given therapeutically. After chemotherapy, vaccines can be used for inoculation to reduce the probability of regrowth of the remaining latent bacilli.

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.