Emergence, Mechanism of Action, Clinical Applications and Challenges of Nanomedicine for Tumor Therapy

Introduction

In 2020, the World Health Organization has reported that there were 18,094,716 new cases of various cancer in the world. (gco.iarc.fr) More and more studies for primary causes of cancer revealed the genetic changes in cells caused cancer and spurred its growth in the final analysis. Instead of being caused by a few genetic mutations that cause cells to grow uncontrollably, cancerous tumors typically arise from the disruption of entire chromosomes. Loss of control over cells that can multiply without limit is the essence of a tumor. Because the gene mutation of tumor cells differs from that of normal cells, tumor cells dive out of the control in the cell cycle, the growth, the proliferation, the deregulation, and the migration.

Patients who have tumor cells that are not part of cancer's primary cause experience severe malnutrition pain, ulcers, hemorrhages, and other problems. Moreover, it significantly raises the risk that a patient will pass away from the illness. Tumor cells will continuously mutate to comfort the environment. It perhaps shows the resistance to medicine, which has been a significant barrier to long-term treatment. So, finding an effective way to kill tumor cells and improve the quality of life of cancer patients with non-invasive treatment has been the expectation of both doctors and patients.

To therapy tumors, researchers have mentioned many therapies. Conventional tumor treatments include chemotherapy drugs, including those used in targeted therapy. According to their various mechanisms of action, chemotherapy drugs are generally divided into eight classes and used to treat tumors in a variety of ways (Table 1).

Table  1.  Chemotherapy drugs are mainly divided into eight classes, according to a different mechanism of actions.

	Advantages	Disadvantages	Typical Drugs	Ref.
Platinum drugs	Almost half of patients can applied	More than 40 specific side effects	Carboplatin, Oxaliplatin, Nedaplatin	[1-4]
Antimetabolic drugs	Inhibit DNA replication to inhibit tumor cells	Influence normal cells’ DNA.	5-Flourouracil, Capecitabine Gemcitabine	[5-7]
Anti-tubulin drugs	Protect cells’ DNA, but inhibit tumor cells growth	Limitation of does, resistance to medicine, and toxicity	Paclitaxel (Taxol), Colchicine, Vinblastine	[8-11]
Topoisomerase I and topoisomerase II inhibitors	Inhibit tumor cells splitting	Toxicity to normal cells	Doxorubicin, Daunorubicin, Etoposide, Dexrazoxane.	[12-17]
Monoclonal antibodies	Specifically combine with tumor cells	Immune system disorder	Gemtuzumab, Alemtuzumab, Rituzumab	[18,19]
Small molecule tyrosine kinase inhibitors	High selective, Less side effects	Inhibit tumor cells grow but can’t kill them	Lapatinib, Imatinib, Sorafenib	[20,21]

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Even though researchers have made a breakthrough in tumor therapy, tumor treatment is still challenging. Since most tumor cells come from healthy cells, they are similar to healthy cells in many ways. As a result, precisely identifying tumor cells and treating them is challenging. In addition, the disability of a tumor makes trouble in therapy because tumor cells will continuously mutate to comfort the environment. It may indicate resistance to the medication that will cause the therapy to fail. Therefore, creating a therapy that can effectively kill tumor cells is important.

In addition, conventional chemotherapy has lots of limitations. As usual, traditional chemotherapeutic small molecules have cytotoxicity, no selectivity will produce toxic side effects. And some medicines are effective in therapy tumors but are insoluble or unstable. Compared with them, nanomedicine can increase the solubility of drugs in an aqueous solution and improve the stability and bioavailability of drugs in living organisms, which can improve performance while lowering harmful effects. Compared with monoclonal antibodies, nanomedicine appears the wider applications. Although monoclonal antibodies appear great potential in overcoming the specific tumor, it maybe not a economic therapy to tumor. In addition, according to statistics, the convert rate of applications from researches is about 5%, so it isn’t an effective and economic therapy. Small molecule inhibitors like tyrosine kinase inhibitors also limited by some factors. Short half-life should be considered when using them to therapy tumor, and it require patients to take medicine in time to maintain drug concentration. And the research and development of novel small molecule inhibitor are difficult because it requires specific site to inhibit^[22-24]. Compared with them, nanomedicine combine the advantages of traditional chemotherapy which is obvious effect and the advantages of small molecule inhibitor or monoclonal antibodies that therapy is specific. In conclusion, despite extensive medical research into the treatment of tumors, developing a medication that targets the tumor while sparing healthy cells is still challenging. Nanomedicine is being used to treat tumors in an emergency.

Nanomedicine uses nano-preparation technology to make active substances into nano-scale particles, or the combination of appropriate carrier materials and active substances to form nano-scale particles and the final pharmaceutical preparations. The properties of nanoparticles (such as stability, blood half-life, etc.) are mainly determined by the physical and chemical properties of the shell material and nanoparticles, while the core often determines the type of drug-active substances loaded by nanoparticles. Since nanoparticles can directly endocytose with target cells or sick cells, nanomedicine has a higher efficacy.

So, nanomedicine perhaps promotes cancer therapy. With its development, there have been various forms of nanomedicine^[25]. One of the main components of first-generation nanomedicine, which is designed to add nanoengineered particles to conventional anti-cancer drugs, is liposomes. Then, newer-generation nanomedicine, which traditionally uses albumin nanoparticles, enhances its effectiveness and minimizes side effects. Various nanomedicine forms were approved, including liposomes, albumin carriers, polymers, and so on^[26-32] (Table 2) .

Table  2.  Advantages and disadvantages of various nanomedicine.

	Drugs	Advantages	Disadvantages	Ref.
Liposome	Patisiran	Less toxicity, decorative, higher medicine stability	Nanoparticles is unstable, easy to solve	[33]
Albumin carrier	Albumin with Taxol	Improve stability to avoid biodegradation	Limitation of mass	[34]
Inorganic nanoparticles	Feraheme			[33]

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With the booming development of nanomedicine, researchers look forward to applying nanomedicine to therapy tumors because of its characteristics including size, stability, and biodegradation. Thus, promoting nanomedicine-based tumor therapy requires an understanding of the mechanisms underlying nanomedicine and its clinical applications.

How does nanomedicine work?

For now, nanomedicine has been widely developed to treat tumor cells. Drug release and polymer biodegradation are two factors that scientists must take into account when designing nanomedicine^[35], so that nanomedicine advances in improved bioavailability by enhancing aqueous solubility^[36], increasing resistance time in the body (increasing half-life for clearance/increasing specificity for its cognate receptors and targeting drug to a specific location in the body (its site of action)^[37].

The medicine release system includes an identification system and a delivery system. It is essential to specifically identify tumor cells to reduce toxicity and the possibility of resistance because it means that nanomedicine can kill tumor cells specifically and effectively but spare normal cells, avoiding tumor cells mutating. Compared with traditional chemotherapy, nanomedicine is possible to overcome this obstruction. Because the blood vessels in tumors are rougher than normal blood vessels, and because of their unique size and surface, nanomedicine may accumulate in the tumor in search of a target. Furthermore, nanoparticles can avoid the immune system, preventing drugs from being cleaned by the body. Both of these can make a great effect and reduce resistance. In addition, nanoparticles also can avoid the immune system so that the drugs would not be cleaned by the body. Nanoparticles' characteristics also allow them to release drugs under control, which could improve the effectiveness of therapy and protect normal cells. Researchers were able to shrink tumors in mice while using smaller doses of the drug to reduce harmful side effects by storing tumor drugs with tiny objects known as nanoparticles^[28].

It is expectable for using this method in the clinic. As usual, liposomes, solid lipid NPs, dendrimers, copper NPs and so on^[26]. With different materials, the methods of release are various. By using micro-phase separation, interparticle cross-linking, and microemulsion, a biodegradable porous polymer with entrapped enzymes and drugs can be reduced to a nano-level. Moreover, super porous stimuli-sensitive hydro gels that can swell or shrink extremely fast. Compared with diffusion, liquid uptake is much faster because liquid molecules are taken up into the hydrogels by capillary forces. Magnetic spheres embedded within the polymer matrix or hydrogels will also be made heat sensitive. By controlling the environmental temperature of the stimuli-sensitive hydrogel, the encapsulated drugs are precisely released^[31]. To make nanomedicine appears more flexible and precise function, we promote nanomedicine in various methods. Through various crystal forming, nanomedicine can appear in different solubilities. Furthermore, we use a variety of carriers to transport and deliver anti-tumor drugs. Dendrimers, liposomes, and solid lipid nanoparticles have all been used^{[29,36,38,39]}.

Nanomedicine is not a stand-alone treatment, but rather a combination with chemotherapies that can reflect their benefits. In a new study that demonstrates an innovative and non-invasive approach to cancer treatment, Northwestern medicine scientists successfully used nanoparticles to damage tumor cells in animal models^[40,41]. It is feasible to design as a nanomedicine due to the high stability and carrier capacity. Nanomedicine is more competitive due to its feasibility in incorporating both hydrophilic and hydrophobic substances as well as a variety of administration methods, such as oral application and inhalation.

Nanomedicine for tumor therapy in clinic

Some nanomedicines are in the experimental stage of development and have received FDA approval. Nanoparticles have been used in medical settings to deliver drugs more effectively by acting as the drug's delivery vehicle. For example, as carries, liposomes have already been available to carry anti-tumor drugs^[37,42]. In addition, biological barriers protected organs and prevented traditional anti-tumor drug delivery. So using nanoparticles as a deliverer is meaningful to the resistant tumor in the brain^[28]. Combined with TAM, a kind of anti-tumor drug for breast cancer, the therapy of nanoparticles shows more specific and less resistance^[26]. Additionally, when using dendrimers as a carrier, it is possible to assess how effectively the drug delivery system is working in comparison to traditional therapy^[36].

As an anti-cancer nanomedicine, paclitaxel, doxorubicin, 5-fluorouracil, and dexamethasone are currently successfully combined with nanoparticles^[43]. Moreover, common nanoparticles include liposomes, iron oxide NP and so on. Doxil, a lipid nanoparticle formulation of the anti-tumor drug doxorubicin, is the first nanodrug and is used to treat ovarian cancer^[42,44,45]. According to nanoliposomes, Adriamycin appears less toxic to the heart but maintains its effect^[46]. Abraxane was developed by Abraxis BioScience®. It is the first bionic nano drug delivery system based on endogenous protein approved for marketing and has been approved for marketing by FDA and EMA. A large number of auxiliary materials are added to improve the solubility of Traditional Taxol preparation. These excipients cause severe hypersensitivity, neutropenia, and neurotoxicity, while Abraxane effectively avoids Taxol^[47]. At the same time, albumin can effectively prolong the half-life of paclitaxel. Then more and more nanoparticles are received, including Au NP, siRNA, Epaxal, and so on. Then more nanoparticles are delivered, such as Au NP, siRNA, Epaxal, and so on. Moreover, nanomedicine is typically administered orally, intravenously, or transdermally^[32,48].

Challenges of nanomedicine

Although there have been significant advances in nanomedicine and numerous approvals, there are still numerous obstacles to its further development (Fig. 1). Firstly, the size of the nanomedicine raises a series of problems. Whether nano drugs cause side effects due to their special size is unknown. Given its volume and surface area, researchers are concerned that its surface may have approved high activity, which might result in the generation of reactive oxygen species (ROS), which can harm proteins, DNA, and membranes^[49]. In addition, nanoparticles may hurt some organs and tissues, such as the lung, liver, and so on. According to studies, Inhalation of nanoparticles in any form leads to the damage to lung^[49], and it is efficient to use in the spleen and liver^[36], which will bring side effects of toxicity. Additionally, nanoparticles will inevitably build up in the liver and spleen, causing damage to these organs^[36,37,49]. It also leads to an inflammatory reaction in the body by the immune system^[49]. It means that although nanoparticles obtain special physical and chemical activity, it can’t be denied that it is hard to monitor and evaluate whether they work because of their tiny size^[49]. It means how to promote nanomedicine in therapy is obstructive. So how solving the problem of its tiny size is one of the keys to broadening the range of therapy tumors.

Figure  1.  Challenges of nanomedicine.

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Secondly, when scientists design nanomedicine, they must take into account the targeting of tumors, release techniques, and the structures of the drug to take into account the advantages and limitations of various materials. According to research, natural nanoparticle structure in more suitable and appears more active than artificial nanoparticles. In other words, natural nanoparticle structures are more readily available, less harmful, and more stable^[37]. And we expect to find more classes of biologically inverted nanoparticles^[29]. But sometimes researchers need biologically inert when delivery. Thus, maintaining a balance between its biologically active and inert components is challenging. Considering its function of delivery and identification, it must appear active in some conditions, but it should keep biologically inert when transported^[49]. However, given that it is inert, it may build up in the blood and liver^[37]. So, how to design nanoparticles with specific active and inert properties should be followed.

At last, what is the unavoidable obstruction is long-term toxicity, which is hard to monitor and predict. Although nanomedicine plays an important role in medicine, the majority of nanomedicine is still in the research and development stage, implying that nanomedicine must be developed on a continuous basis^[35]. Scientists should generally accept the standard of evaluation and design, and it should be economical, useful, and scientific. Considering most nanoparticles are inert, the accumulation of nanoparticles may cause an unexpected issue. It means that the problem is challenging to identify at a young age because it is inert. In the meanwhile, various nanoparticles are complex, it is difficult to conclude their toxicity of them. As a result, further studies are needed to evaluate the safety of nanoparticles. Therefore, ongoing monitoring of long-term toxicity is necessary to ensure its safety.

Prospects

Nanomedicine has shown great potential in cancer therapy due to its unique characteristics. The present article reviews the working principle, clinical application, and future challenges of nanomedicine. However, there are still many obstacles to its application. How to reduce the off-target rate and how to accurately evaluate its toxicity remain to be solved.

Nanomedicine will undoubtedly be the most promising future development path for cancer treatment, even though it has not yet been approved for use in the treatment of cancer due to its safety and side effects. Due to the rapid development of nanomedicine, it is not possible to summarize all aspects of nanomedicine in this paper. Nanomedicine has been given the go-ahead to be used, but it must be used in conjunction with conventional therapy when used to treat cancer. With the deepening of research, nanomedicine is expected to realize the functions of specific tumor recognition, controlled drug release, avoidance of drug resistance, and no side effects.