3.2.2. Nystatin and Nyotran
Like Amphotericin B, Nystatin is a polyene antibiotic. However, due to its systemic toxicity and low intestinal permeability, the therapeutic application of Nystatin has been limited to topical use in mucocutaneous (oral) and cutaneous (vaginal) forms of candidiasis
[155][56].
To overcome these limitations, lipid-based nanotechnologies have been applied to Nystatin as a multilamellar liposome, known as Nyotran, used in treating systemic fungal infections
[156][57]. With the liposomal formulation, Nyotran shows reduced toxicity, improved pharmacokinetics, and better tolerability
[157][58]. Another clinical report also stated that Nyotran was active in some patients in which Amphotericin B treatment failed
[158][59].
3.2.3. Inhaled Liposomal Antimicrobial Medications
Besides the most common routes of liposomal drug delivery, such as oral, typical, and parenteral, the use of inhaled liposomal dosage form for treating respiratory diseases and/or infections has been used increasingly in clinical practice
[159][60]. Inhaled liposomal dosage forms offer potential advantages for the treatment of respiratory infections including targeted delivery, reduced systemic toxicity, improved efficacy, and minimized side effects
[160,161,162][61][62][63].
Amphotericin B, as the common treatment for pulmonary fungal infections, is limited by high mortality in achieving the minimum inhibitory concentration in the lung
[163][64]. To address these challenges, clinical studies have explored the administration of a liposomal amphotericin B parenteral formulation alone or with amphotericin B deoxycholate through nebulization
[164][65]. Nebulization is the method that converts medications into fine mist for inhalation, which has shown promise in enhancing the delivery of amphotericin B and combating pulmonary fungal infections. Apart from the nebulization, pressurized metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs) are also being used for drug delivery, but each device requires different formulations to ensure successful drug delivery into the lung
[165,166,167][66][67][68].
3.3. Pain Management
Acute pain mostly happens following tissue damage associated with surgery, also known as acute postoperative pain, and chronic pain would persist during the healing process for at least three months after the surgery
[168][69]. Additionally, chronic pain could produce an enormous financial burden for the patients
[169][70]. While chronic pain is not life-threatening, it may have a lasting impact on functioning and influence the quality of life of the patients.
An ideal postoperative pain management should use a multidisciplinary approach to interfere with different pain propagation and perception mechanisms
[170][71]. Moreover, an effective pain management control method is to shorten the inpatient time, avoid opioid dependence or addiction, and reduce the mortality
[171][72]. In addition, regional and local anesthesia play an important role in postoperative pain control, as they block the afferent neural stimuli from the surgical area in order to reach the effective analgesic effect
[172][73]. Local anesthetics, such as bupivacaine, provide more successful pain control than opioids and are widely used for preemptive infiltration during the postoperative period with prolonged duration of action
[173][74].
3.3.1. Exparel
Two FDA-approved liposome formulations (DepoDur and Exparel) have been used for pain management. Exparel is a multivesicular liposomal formulation of bupivacaine being developed for wound infiltration in patients with hemorrhoidectomy and bunionectomy
[177][75]. Exparel is composed of dierucoylphosphatidylcholine (DEPC), which is a novel phospholipid excipient, and other lipid components, including DPPG, cholesterol, and tricaprylin.
3.3.2. Liposomal Cannabidiol
Cannabidiol (CBD), a phytocannabinoid discovered in 1940, can be used to treat a number of diseases, such as Alzheimer’s disease, Parkinson’s disease, and chronic pain
[179,180,181][76][77][78]. The traditional form of CBD has low oral bioavailability and off-targeting effects, thus impeding its optimal therapeutic index
[182][79]. Nanocarriers have been used for the targeted delivery of various phytocompounds, including CBD, and can improve the stability of phytocompounds, enhance bioavailability, and increase solubility and permeability
[183][80].
3.4. Vaccination
Conventional or classical vaccines are based on the use of whole or killed bacteria or viruses to mimic their natural interaction with human immune systems
[186,187][81][82]. Vaccines remain the most cost-efficient way to defend infectious diseases. Nonetheless, several challenges are yet to be solved, such as the identification of the antigen candidates, ability to induce appropriate immune responses for protection, cross-protection against different strains of pathogens, and route of administration
[188][83]. In vaccine development, the ability of initiating the innate and adaptive immune responses is essential. To elicit a sufficient immune response against the antigens, choosing the appropriate immunostimulatory molecules (e.g., adjuvants) and the efficient delivery platform matters. The adjuvants could not only help prolong the exposure time of the vaccine molecules to the antigen-presenting cells (APCs) but could also interact with APCs and trigger immune responses by themselves
[189,190][84][85]. Liposomes were first investigated as vaccine adjuvants and a delivery platform in 1974
[191][86]. Due to their flexibility and versatility, immuno-stimulation induced by liposome-carried vaccines can be modified by various factors including liposome composition, size and homogeneity, charge, and location of antigens and/or adjuvants
[192][87]. It is well noted that the versatility of liposomes in cargo selection plays a pivotal role in vaccine delivery system
[193][88]. Water-soluble antigens such as proteins, peptides, and nucleic acids are encapsulated in the aqueous core of the liposomes, while the lipophilic substrates such as adjuvants, glycolipids, and lipopeptides are entrapped in the lipid bilayers of the liposomes. The antigens could also associate with the surface of the liposome by absorption or covalent binding
[194][89]. Regardless of where the antigens are present (in/on liposomes), the immune responses can be induced by the liposomes, which are phagocytosed by the macrophage and the antigens are processed and presented on the macrophage surface with either the MHCI (major histocompatibility class I) complex if antigens end up in the cytoplasm or the MHCII if antigens end up in the lysosomes. Consequently, the antigen peptides on the MHC complex are recognized by the cytotoxic T lymphocytes (CTLs) and bind to the T cells. Specific cytokines are secreted from the T cells, interacting with B cells and then stimulating B cells to produce antibodies
[195][90].
4. Conclusions
The pharmaceutical applications of liposomes are not limited to what have been mentioned above. Liposomal drugs have also been used for photodynamic therapy
[204][91], bacterial infections
[205][92], and cardiovascular diseases
[206][93]. In addition, liposomes have been explored for nanotechnologies as signal enhancers in medical diagnosis
[207][94], solubilizers for various ingredients, and penetration enhancers in cosmetics
[55][95].
Because of the unique characteristics of liposomes, they have also been developed as carriers for brain delivery of bioactive constituents and used for treatments of various central nervous systems disorders such as Alzheimer’s disease
[208][96], ischemic disease
[209][97], and Parkinson’s disease
[210,211][98][99]. However, to fulfill their clinical translation, the liposomal formulations are required to undergo additional studies to further prove their effectiveness, such as to evaluate the combinations of bioactive molecules, measure the dosage of bioactive molecules administered, and perform assessment in patients with different central nervous system disorders
[212][100].
The liposome exhibits various advantages, such as reducing the side effects, improving the pharmacokinetics, and enhancing the delivery efficiency to target sites as compared to free (unentrapped) drugs. However, liposomes still face some challenges. One critical issue is drug leakage from the liposome during the circulation before it is navigated to the tumor site
[213][101]. Unwanted leakage would not only yield suboptimal circulation times but also release the cytotoxic agents prematurely, damaging the healthy organs/tissues
[213][101]. The primary cause of liposomes’ drug leakage is serum proteins, such as lipoproteins, which can interrupt the integrity of liposome bilayers
[213,214][101][102].
While liposomes have shown potential to mitigate systemic toxicity associated with delivered therapeutic agents, systematic evaluation of side effects stemmed by liposomal nanocarriers in preclinical and clinical settings remains crucial
[228,229][103][104]. Organ toxicity is a major concern of liposomal nanodrugs
[230][105] because they prefer to accumulate in certain organs, such as the liver and spleen, affecting the tissue-specific functionality and potentially causing toxicities
[231][106]. In addition, liposomes may interact with cell membranes, which can alter cell permeability and integrity, ultimately causing cellular damage
[232][107]. Addressing these safety concerns requires strategic refinement and optimization. The formulation of liposomes plays a pivotal role in liposome-induced cytotoxicity. By further optimizing and modifying liposome composition, size, and surface properties, interactions with specific organs could be minimized. Additionally, efforts in enhancing the targeting specificity of liposomal dosage form are research directions that can greatly limit the off-target organ distribution, thus further reducing the systemic toxicities.