Liposomal Nanoparticles: A Viable Nanoscale Drug Carriers for the Treatment of Cancer

Abstract

Cancer immunotherapy is emerging as a promising therapeutic modality for achieving highly efficient therapeutic performance while avoiding tumor metastasis and relapse which are most common outcome of traditional cancer therapies (surgery, chemo and radiotherapy). Liposomal nanoparticles may be an ideal platform for systemic immune modulator delivery. Liposomes, the lipid bilayer vesicles, are biocompatible biodegradable carriers that are extensively used for the delivery of both hydrophilic and hydrophobic bio actives. The advance features like structural fabrication of liposome for ligand anchoring, long-circulation, and stimuli-responsiveness are helpful for the demand of clinical and industrial uses. Recent studies have reported the manifestations of liposomal newer developments in cancer treatment. Presentchapter discusses the most recent advances in liposomal nanoparticles for cancer therapy along with ligand targeted, stimulus targeted and autophagy modulation by liposomal nanoparticles for cancer treatment.

1. Introduction

Cancer is a huge and enormous health challenge of the current century, in which the active cells of body become abnormal and multiply at uncontrollable rate. The major cause for this disease is environmental toxins which further damage the DNA structure. As per the report of World Health Organization (WHO) 2018, cancer is the second most leading cause of deaths around the world. Approximately 9.5 million people had died due to different types of cancers in a year. A continuous increasing in new patients and mortality rate due to cancer clearly indicates that there is an urgent need for the development of new techniques for its treatment. One of the effective and major treatments of cancer is chemotherapy with anticarcinogenic agents. But due to lack of appropriate sensitivity and specificity, chemotherapy with anticarcinogenic agents is ineffective. Also, this method of treatment of the cancer has been restricted due to its ill effects [1].

There are various traditional medicines which show poor materiamedica, restricted pharmacokinetics and deadly toxins, which administered controlled use of these drugs. To deal with these problems and upgrade the remedial indexes of the medicine, the emerging fields of nanotechnology and nanomedicine have made denoting development in disclosure, interpretation and medication of numerous diseases at the initial level [2]. In the current scenario, use of liposomes nanoparticles has made it feasible to reduce the toxicity and enhance the pharmacology parameters, such as delivery, extended transmission time, focused composed discharge, increased intracellular concentration, upgraded solvency and stability of drugs in the living being. All these important points have been attained by using the delivery systems of medicines with nanoparticles ranging from 1 to 100 nm diameter, where a huge facet results in expanded cellular communication and numerous modifications of facet attributes. Further, by rendering various medicines, medication using nanoparticles have also facilitated synergetic treatments and refrained medicine protection [3].

Present article is an attempt to summarize the findings of the exploration and fabrication of liposomes and various attributes of liposomes. An attempt has also made to analyze the availability and development of liposomal medicines, being used for cancer treatment in the market. Eventually, a report related to fortuities and disputes related to the utilization of nanomedicines related to liposomes will be deduced, that can be used to highlight it as a crucial issue for the future research of the scientists. The result of it can be the abolition of the restrictions and nourishing the beneficial points. They represent an expansive extent of clinical stage nanotherapeutics because of their degradable, compatible, non-poisonous, and insusceptible formation. The amphiphobic phosphatide layer of liposomes are almost similar to the marsupial cell layer which enables a systematic interaction between nanoparticles and cell layer. In this way, it enhances the feasible cellular intake. Moreover, these nanoparticles may be included with molecules for extended productivity and particularly selecting injured cells. This improves pharmacological medicine of liposome and their capacity to traverse target cells, coming to absorption of interior cells, thus, reducing toxicants and enhancing medication viability. Liposome embodiment may decrease sedate endorsement by the immune and excretory organ, thus increasing transmission period in the blood and enhancing their accessibility [4]. Another profit of nanoparticles in their thermo heat sensitive aspect, i.e., arise of degrees (40–41°C) in packing leads to changes in the bilayer, which soothes the discharge of the encapsulated medicine. These thermo-devices favor the discharge of a great amount of the anticancer drug to a heat-treated location in the tumor, when an external source of heat is used, thus keeping away the harm to the bordering normal tissue [5].

2. Liposomes mediated delivery of anticancer drugs

Liposomes are dual layered spherical cells which include saturated fats and cholesterol. They create a minimum of one lipoid dual layer in water, surrounding a liquid base that may enclose both hydrophilic medicines and hydrophobic compounds submerged via means of lamellae by Van der Waals. Phospholipids are amphipathic liquids that include glycerol molecules certain to a group of phosphate (PO₄²⁻) and dual chains of fatty acid which can be moistened or un-moistened. The phosphate has also a close bondage with an organic particle, e.g., mono-ethanolamine or choline. Lecithins are key ingredients which provide distinctive features to liposomes, such as how the compounds are encapsulated and how they function inside the body. Both liposomal and plasmalemma can coincide during the release operation as phospholipids are the main biological components of tissue membrane [6].

3. History of liposomes

The discovery of the cell by Anthony Van Hook in the late seventeenth century prompted a lot of questions about how cells are formed. The presence of phospholipid dual layers in plasma layers was discovered by Ten, Gorter and Grendel in 1925. Later, the dual layers clutter layer model was later described by Singer and Nicolson to explain the behavior of plasma layers phospholipids. These research-based studies and hypothesis captivated the attention of other scientists to nanoparticles derived from fats. Then, it was in 1965 when Alec D. Bangham discovered liposomes and were named as “banghosomes”. Later, “banghosomes” were renamed by Gerald Weissmann as liposomes in 1968. Liposomes belonged to such class of therapeutic nanoparticles used in cancer treatment which was the first to get approval worldwide [7].

4. Size and structure of liposomes

The diameter of liposomes starts from 20 nm to greater than numerous hundred micrometers. The size of the particle affects their material medica, tissue extravasations, dispersal of tissue, hepatic cirrhosis, elimination from kidney, and rate of dispensation from the location of injection. Liposomes of an average diameter ranging from 100 to 150 nm can enter into the liver epidermis, subordinate formation of lymphoids, or the contexture of tumors. As it were liposomes with one of these breadths which can simply elude from blood arteries that pervade tissues, e.g. heart, lung and kidney. In contrast, molecules having diameter lower than 10 nm may filter via the glomerular artery and may not re-assimilate. It can be noted that liposomes with a diameter of 100–150 nm are the most important for cell uptake. As the liposome diameter is decreased to 50 nm or less greatly decreases dispensation of endocytosis, so the system endocytosis is also particularly important. Thus, the liposomes which are within the range of 50 nm −100 nm, keep away endocytosis and take extended blood transmission time. Subsequently, the ideal range size of liposomes ranges between 80 and 150 nm [8].

Liposomes basically consist of phospholipids. Phosphatides are a form of liquids, which are in similarity with triglycerides. There is a pillar of difluoride and two chains of hydrophobic in the formation of Phosphatides. In this way Phosphatides are considered amphiphilic atoms (Figure 1).

Figure 1.

The non-polar and polar components of Phosphatides.

Phospholipids liposome membrane mainly contain phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and sphingomyelin which are amphiphilic in nature and have a strong propensity to create specific configuration in water. The primary cause of this appearance is that phospholipids include two hydrophobic tails (fatty acids) and a hydrophilic head (phosphate molecule). The phosphate group gather interatomic with H₂O polar atoms, whereas the hydrophobic tails elude from water atoms and interact with each other.

5. Classification of liposome

The size, number of phospholipid bilayers, mix method, and production procedure of liposomes can all be used to classify them. Liposomes can be categorized into three sizes: tiny, medium, and giant, based on their size. Vesicles can be unilamellar, oligolamellar, or multilamellar, depending on the number of membrane layers. In this respect, it can be stated that the unilamellar vesicles are phospholipid bilayer-containing liposomes that range in size from 50 to 250 nm, whereas multilamellar vesicles are much bigger, approximately 0.5–1.5 μm, and also comprise various phospholipid bilayer membranes. Diverse liposomes have definite system of preparation. In the majority of these production techniques, lipids are solved in order to produce liposome membranes using a specific solvent (such as methanol, chloroform etc.). Other techniques for producing liposomes include French pressure cells, sonication, reverse phase evaporation, freeze-drying and membrane extrusion [9].

6. Therapeutic applications of liposomes

In comparison to the existing formulations, liposomes provide superior therapeutic efficacy and safety [10]. Some of the main the remedial implementation of liposomes in the delivery of remedial medicines include:

6.1 Site-avoidance drug delivery

The cytotoxicity of anti-angiogenic medicines of cancer is credited to their narrow remedial index. By decreasing the delivery of medicine to normal cells and by enclosing it in liposomes, the remedial index can be enhanced. For example, doxorubicin has a severe side effect of toxicity related to heart, but when composed as liposomes, the poisonous quality is minimized without any alteration in the therapeutic activity [11].

6.2 Target specific drug delivery

Delivery of a larger fragment of the medicine to the location of tumor/cancer, can be achieved by particular targeting of the location, thereby reducing the drug’s exposure to normal tissues. On systemic management, it was found that the expanded circulation of immunoliposomes can recognize and hold together the target membranes with greater accuracy. For example, in patients with repetitive osteogenic sarcoma, an enhanced tumoricidal activity of white blood cells was observed when muramyl peptide derivatives were formulated as liposomes and managed systemically [12].

6.3 Intracellular drug delivery

Enhanced delivery of prospective medicines to the cytoplasm, where sedate receptors are present, can be achieved by utilizing liposome sedate conveyance framework. Generally, N-(phosphonacetyl)-L-aspartate) is ineffectively taken up into cells. Such drugs when enclosed within liposomes, showed greater action against ovarian tumor cell lines as compared to free drug [13].

6.4 Drug delivery with sustained release

Liposomes produce maintained discharge of target medicines to accomplish the maximum remedial efficiency, which requires an extended plasma concentration at remedial levels. Medicines such as cytosine Arabinoside can be enclosed in liposomes for continuous liberation and improved ejection rate in living organism [14].

6.5 Intraperitoneal administration

Cancer which develops in the spinal cavity can be cured by regulating the medicine to spinal cavity. Nevertheless, the swift dispensation of the medicines from the intra-peritoneal cavity results in decreased quantity of medicine at the infected location. Medicines enclosing liposomes have lower acceptance rates than free medications, and they can deliver the maximum amount of medication in a prolonged manner to the affected area [15].

6.6 Vaccine immunological adjuvants

Liposomes can be utilized to improve the response of immune system by compressing the supplements. Depending on an antigen’s lipophilicity, they can be accommodated by liposome in the liquid cavity or assimilate with the dual layers. Liposomes were used for the first time as immunological adjuvants, to increase the immune response of diphtheria toxoid [16].

7. Mechanism of action of liposome

A liposome contains a particular place inside a lipid hydrophobic cell. Hydrophobic substances are easily diluted with the lipid membranes. In this manner, hydrophilic and hydrophobic molecules both are carried by liposomes. Subsequently, the drug’s placement will rely on its biophysical characteristics and lipid structure. The lipid bilayers combine with other bilayers of the cell membrane to deliver necessary drug molecules to the site of activity, thereby releasing the liposomal content [17, 18]. Following are the steps which are involved in liposome action of drug delivery:

7.1 Absorption

Absorption of liposomes to layers of cell are the reason of its contact on the layer of the cell.

7.2 Endocytosis

Absorption of liposomes on the surface of the layer of the cell followed by swallowing and internalizing them into the liposomes.

7.3 Combination

Direct transport of the contents of liposomes into the cytoplasm is achieved by combining the lipid dual layers of liposomes with the lipoidal cell membrane by lateral diffusion and mixing of lipids.

7.4 Exchange of lipid

Lipid transfer proteins in the cell membrane quickly recognize liposomes and start lipid exchange because the phospholipids in the liposomal lipid membrane and those in the cell membrane are identical. For instance, cancer cells absorb a large amount of fat to meet the requirement of rapid development. They perceive the anti-cancer drug-loaded liposomes as a potential nutritional source. They are submerged when a liposome focuses on them. When the anti-cancer medications are released from the liposome into the area, the medication starts to kill cancer cells [19].

8. Liposomal formulations for treatment of cancer

The following are the most current clinical results using different liposomal drugs to treat different solid tumors:

8.1 Daunorubicin and doxorubicin

Doxil® is the trademark for the primary PEGylated Liposome Technology medication delivery technology. It comprises doxorubicin hydrochloride, an anthracycline-family anticancer drug that is capsuled. It helps cancer cells undergo caspase-dependent apoptosis brought on by oxidative DNA damage. It inhibits topoisomerase II, an enzyme necessary for the division and growth of cancer cells. Free radicals, reactive oxygen species that can harm membrane structure and result in lipid peroxidation, are also produced by this enzyme [20].

8.2 Paclitaxel and docetaxel

Paclitaxel inhibits the growth of tumor endothelial cells when combined with beta microtubules. As paclitaxel is insoluble in water, therefore, dehydrated ethanol and polyethoxylated castor oil in a 1:1 (v/v) ratio are utilized as preparation instruments, despite the fact that it causes harmful side effects such neuro adulteration, hyperlipemia, and hypersensitivity reactions. Several cremophor-free liposomal paclitaxel (LPTX) synthesis has been permitted by FDA to avoid these drawbacks. Some of the examples include: (i) LEP-ETU, a traditional anionic nanoparticle with an estimate of about 150 nm (ii) EndoTAG™, a cationic liposome structure of lipoid-submerged with chemotherapy drug, which links with negatively charged cells of tumor endocardium reducing the blood supply of the tumor and (iii) Lipusu® a formulation prepared by utilizing film scattering strategies followed by a lyophilization method. Formulations resembling liposomes without the cremophor, such as Genexol-PM, a low-density lipoprotein receptor-binding nanocomposite amphiphilic structure of paclitaxel and PTX-LDE, nanoparticle with lipid core compressed with paclitaxel, which accumulates in the tumor tissues [21].

8.3 Docetaxel

Docetaxel, which is a polymerized taxane equivalent and an antimitotic medium, joinsitself to the beta tubulin. It is also the reason of stabilization of tubulin polymerization. This stabilization prevents mitosis by breaking microtubules and capturing the G2/M phase of cell cycle. It is frequently used in the treatment of a number of solid tumors but is ineffective in water. The docetaxel (Taxotere) that is now on the market is prepared in ethanol and Tween 80 since it is insoluble in water. However, this substance has been linked to fluid retention over time, severe hypersensitivity reactions, and infusion-related toxicity. To prevent such unfavorable side effects, a number of free Tween 80 and ethanol delivery technologies, including polymeric micelles, nanosomes, nanospheres and protein, have been created and clinically tested [22].

8.4 Mifamurtide

The European Union, Switzerland, and other nations have approved Mepact®, also known as liposomal mifamurtide formulation (liposomal muramyl tripeptide phosphatidylethanolamine), for the treatment of osteosarcoma [23].

8.5 Vincristine

To overcome the dosage, pharmacokinetic, and pharmacodynamic restrictions of non-liposomal vincristine, vincristine sulphate, a semi-synthetic chemotherapeutic drug, has been compressed in sphingomyelin/cholesterol nanoliposomes. Due to its demonstrated safety, the FDA has authorized Marqibo® (Vincristine injection dosage form). Additionally, it demonstrated tolerance as well as improved mononuclear phagocyte system-associated tissues and organs, such as non-Hodgkin lymphomas, vincristine cell uptake, penetration, and concentration [24].

8.6 Cytarabine

Cytarabine is available in a slow-release dose form called liposomal cytarabine (Depocyt®), which causes cytotoxic quantities of the drug to last for at least a week in the cerebrospinal fluid. However, non-liposomal cytarabine is only sustained for 24 hours. When used under supervision as first-line therapy and in conjunction with dexamethasone, Depocyt ® has acceptable toxicity. All of this strongly suggests that it might be crucial in the future for enhancing outcomes for kids with acute lymphoblastic leukemia [14].

9. Engineered tumor target liposomes

In view of its potential for safety and efficacy for site-specific medication administration, liposomes are regarded as the model biomembranes. Cancer has a complicated microenvironment, thus developing tumor-targeted liposomes that include features like remote control or tumor stimuli response to promote tumor extravasation and specific ligands for efficient intracellular localization within tumor cells is necessary [25]. Acute myelogenous leukemia has been treated with folate-anchored Dox-loaded liposomes following all-trans retinoic acid stimulation of folate receptors [26]. A peptide analogue of ApoE3 targeted to low density lipoprotein receptor made it easier to penetrate the blood–brain barrier for dual targeting using distinct ligands, which improved the targeting capabilities of transferrin MAb functionalized liposomes [27]. The PC-3 tumor cells (a prostate cancer cell line) showed observable cellular accumulation in response to the RPARPAR liposomes loaded with doxorubicin, which resulted in greater tumor growth suppression [28]. Multidrug resistance mechanism may not apply to engineered liposomes (due to Pglycoproteins that pump out doxorubicin or vincristine) [29]. By using pH-, temperature-, or photosensitive engineered liposomes, also known as stimuli responsive liposomes, to trigger or control drug release upon effective tumor microenvironment utilization, it is possible to ensure higher accrual of such multidrug-resistant/susceptible drugs after their internalization into target cells [30]. When compared to a control liposome, those loaded with Doxorubicin and Magnevist (a magnetic resonance imaging agent) and anchored with hyaluronic acid-ceramide demonstrated greater cell uptake as a result of the interaction between hyaluronic acid and CD44 receptors. Tagalakis et al. [31] reported serum-stable PEGylated liposomes coupled with peptide for the transfection of plasmid DNA and found that PEGylation increased self-assembly and cell uptake by receptor-mediated endocytosis. Gao et al. [32] focused their work on the characterization, therapeutic effectiveness, advances in antibody engineering, and potential applications of monoclonal antibody-anchored liposomes for cancer chemotherapy. PEGylated immunoliposomes with anti-human epidermal growth factor receptor antibodies, like cetuximab, accumulated more in glioblastoma multiforme [33]. Noble et al., [34] provided a thorough analysis of the challenges presented by modified liposomes for the treatment of cancer, including quicker blood clearance, queered targeting caused by RES absorption, and poor tumor penetrability. Dequalinium and epirubicin-loaded liposomes with a positive charge showed increased cytotoxicity in vitro and anticancer effectiveness in animals [35]. Similar to this, dequalinium displayed efficient mitochondrial targeting in topotecan-loaded liposomes, enhancing therapeutic efficacy in vivo in comparison to untargeted liposomes [36]. Triphenyl-phosphonium, a mitocancerotropic drug, and folic acid coupling to DOX-loaded liposomes have both been shown to improve tumor targeting potential through greater accumulation in mitochondria [37].

10. Conclusions and future perspectives

Since its discovery in 1964, liposomes have a broader range of applications. Whether they are man-made or naturally occurring, the lipids that make up liposomes each have different uses, benefits, and drawbacks. Traditional pharmaceuticals must pass through numerous obstructions and hostile environments in the body that degrade them in order to reach the desired location, including the blood brain barrier, the intestinal wall barrier, the liver, the bloodstream’s proteins and enzymes, and the stomach’s acidity. Pharmacological substances in the form of liposomes can travel through the body and act as a means of transport to get to the desired tissue, organ, or receptor. Phosphatidyl-choline is the most widely utilized lipid component due to its neutrality and affordability. As previously mentioned, studies have shown that encapsulating anticancer medications like daunorubicin, doxorubicin, and cytarabine in liposomes has therapeutic advantages.

Liposomes can be categorized based on their size, shape, composition, and manufacturing procedure. Greater therapeutic effectiveness against infections, enhanced drug-target selectivity, and improved pharmacokinetics and pharmacodynamics are all advantages of employing liposomes as a drug delivery vehicle. On the other hand, the disadvantages include problems with stability and short shelf-life, problems with encapsulation effectiveness, and problems with sterilization. Certain lipids, particularly charged lipids, become poisonous in increasing concentrations. However, if a therapeutic drug is consumed in excess of a particular amount, it may turn toxic and seriously harm one or more body organs. As a result, the liposome formulation needs to be carefully and effectively created. Future research will be able to improve on existing platforms and solve the current translational and regulatory limits by having a better understanding of the advancements in liposomal technology to date and the hurdles that still need to be overcome. The way liposomes interact with cells affects how well a medicine is delivered. In recent years, liposomes have been used as drug delivery vehicles with a few commercially available formulations that demonstrate increased effectiveness. For further translational success, it will be necessary for professionals involved in manufacturing, pharmaceutical design, cellular interactions and toxicology, as well as preclinical and clinical evaluation, to communicate with one another and work together. According to scientific evidence, medicine delivery via liposomes has a bright future.

Conflict of interest

The authors declare no conflict of interest.