Trends in tumor treatment

The area of Brain Tumor Treatment generates a high interest among scientist and researches . Here we decided to gather some of the most promising from our point of view approaches, which we will try to summarize at the end of the page in order to make the inference regarding the today's trends in this field. We stopped at immunotherapy as dynamically developing trend in a brain tumor treatment. 

Immunotherapy

A major function of the immune system is to recognize foreign objects (viruses, bacteria, parasites, splinters, and anything else that isn’t supposed to be in your body) and destroy them. Immune cells do this by recognizing specific targets on the surface of the object.  Cancer cells are abnormal and may be recognized as ‘foreign’ by immune cells. Immune cells can then kill these cancer cells. Unfortunately, the immune system is also deeply involved in the development of cancer.  While this is certainly not something that is good for the person, the cells are not 'thinking' about what they are doing, and are only really doing what they are being told to do.  Immunotherapy is listed as one of brain tumor treatments which can slow the growth of tumor cells but not necessarily helps patients with high grade brain tumor, survive. Obviously this kind of treatment it is still part of clinical trials where doctors and scientists keep researching for its benefits and the way can (if) treat brain cancer. But nonetheless there are some promising options that immunotherapy offers that are already approved to use for treatment. Bevacizumab (Avastin®), a targeted antibody that disrupts tumor blood vessel formation, is currently approved for patients with recurrent glioblastoma, while the targeted antibody dinutuximab (UNITUXIN®) is approved for children with neuroblastoma, a cancer of the nervous system. ^[11]

[11]

Vaccine therapy

The vaccine therapy we also mentioned on the previous page Group2: Brain tumor treatment is another clinical trial for cancer treatment on brain. In fact scientists are working not only to use vaccines as a treatment option but also as a way to prevent brain tumor and the creation of cancer cells. The purpose of cancer vaccines is to stimulate the body's defenses against cancer by increasing the response of the immune system. Our immune system provides a dynamic protective system against disease from foreign pathogens and from abnormal body cells. Cancer cells are, in essence, normal body cells that have sustained mutations and no longer function properly. Tumor vaccines usually contain proteins found on or produced by cancer cells. By administering forms of these proteins and other agents that affect the immune system, the vaccine treatment aims to involve the patient's own defenses in the fight to eliminate cancer cells. There are many strategies in immunotherapy. Some strategies are considered 'passive' while others are 'active'.  ^[10] [12]

• Passive immunotherapy 

  This type involves giving antibodies or mature T cells to the patient to attack the cancer cells. This type of therapy does not induce permanent change in the patient's own T cells, but may be effective in a variety of cancers including leukemia and breast cancer. One of the most widely used cellular immunotherapy strategy is the transfer of immune cells from a healthy donor to a recipient who has had a bone marrow transplant or other stem cell transplant. ^[10] [12]

• Active immunotherapy 

  This type strategies include tumor vaccines, because they directly stimulate the patient's own immune cells to have a long-lasting response against the cancer. All of these strategies aim to stimulate the antigen presenting cells (APCs) and T cells in some way. ^[10] [12]

After getting familiar with immunotherapy approach, we have to figure out how actually the treatment targets the brain because it has to cross the blood brain barrier (BBB).  And it is an extremely challenging topic for researchers nowadays.

Approaches to Brain-Tumor Targeted Drug Delivery

In order to reach a tumor many approaches require a treatment to be delivered directly to tumor cells in some way.

For instance a chemotherapy approach involves the drugs to destroy tumor cells, generally by stopping the tumor cells ability to mature and divide. However, severe side-effects, including nerve damage, nausea, hair loss, vomiting, infertility, diarrhea, skin rashes, and insomnia are major limitations[1]. As one can see the approach above is pretty harmful for the patient, that is why delivering of chemotherapeutic drugs into the brain is a challenging task today. One of the existing noninvasive methods is ultrasound.

Several invasive methods such as intra-cerebrospinal fluid, intra-thecal, and intra-tumoral injections are also used[2]. However, these methods suffer from severe neurotoxicity and neuropathological consequences. 

 For better understanding of the drug delivery process through a BBB it is useful to know how actually the transport mechanisms at the BBB work.

Transport mechanisms at the BBB

 They can be divided into three major categories:

• passive diffusion
  The BBB allows the passage of water, oxygen, carbon dioxide, and lipid-soluble small molecules by passive diffusion, a concentration gradient dependent process. 
• transporters mediated transcytosis (TMT) 
  TMT is substrate selective in which carrier facilitates the transport of molecules by the influx and efflux transporters, and carrying substances in and out of the CNS, respectively. A large number of chemotherapeutic drugs are removed out of the CNS due to the efflux transporters (P-glycoprotein, multidrug resistance-related proteins, and breast cancer resistance protein) expressed at the apical side of the BBB.
• fluid phase transport by vesicles 
  Fluid phase transport by vesicles allows the transport of large molecule drugs into the CNS and includes two mechanisms; adsorptive mediated transcytosis (AMT) and receptor-mediated endocytosis (RME). AMT is mediated by electrostatic interactions between the positively charged delivery systems and the negatively charged brain capillary endothelial cell membrane surface regions. The mechanism of RME is based on the interaction of targeting molecules on drug delivery systems with brain receptors such as transferrin, low-density lipoprotein, and insulin, etc. Most macromolecules are delivered to brain cells across the BBB via these specific receptors. In the CNS targeted drug delivery, the RMT pathway has been actively used because of the higher specificity it can provide.[9]
  
  

                                                                    Nanocarriers-based strategies for crossing the blood-brain barrier (BBB).

Down below several techniques are performed in more details regarding brain tumor treatment via crossing BBB.

Nanotherapeutic Approaches

Nanocarriers are colloidal systems in the nano size range and have been considered as one of the most promising approaches in brain-tumor targeted therapy due to their unique properties[5]. Compared to conventional drug formulations, nanoformulations offer significant advantages such as drug protection from in vivo and in vitro degradation, increase the drug solubility and provide high drug loading, targeted drug delivery by incorporation of ligand molecules, versatile surface modification chemistry, homogeneous size distribution, and flexibility in providing controlled or stimuli-responsive drug release behavior [6][7]. Due to these advantages, several nanocarrier systems such as polymeric nanoparticles (NPs), liposomes, dendrimers, nanomicelles, polymerosomes, gold NPs, nanogels, quantum dots, and magnetic NPs, etc., are explored in brain-tumor targeting approaches [5][8][9]. A schematic representation of these nanocarriers is shown by the picture.

Nanocarrier systems for brain-tumor therapeutic approaches.

The second approach is Ultrasound.

Ultrasound

There is an increasing interest in the use of ultrasound to enhance drug delivery to the brain and central nervous system. Ultrasound can be non-invasively delivered to the brain through the intact skull. When combined with preformed microbubbles, ultrasound can safely induce transient, localized and reversible disruption of the BBB, allowing therapeutics to be delivered. Investigations to date have shown positive response to ultrasound BBB disruption combined with therapeutic agent delivery in rodent models of primary and metastatic brain cancer and Alzheimer's disease.[3] 

We have also found a research using a combination of ultrasound and inranasal technique. Intranasal (IN) administration itself  is a promising approach for drug delivery to the brain, bypassing the BBB; however, its application has been restricted to particularly potent substances and it does not offer localized delivery to specific brain sites.

Focused ultrasound (FUS) in combination with microbubbles can deliver drugs to the brain at targeted locations. The approach propose to combine these two different platform techniques (FUS+IN) for enhancing the delivery efficiency of intranasally administered drugs at a targeted location. After IN administration of 40 kDa fluorescently-labeled dextran as the model drug, FUS targeted at one region of mouse brains was applied in the presence of systemically administered microbubbles. To compare with the conventional FUS technique, in which intravenous (IV) drug injection is employed, FUS was also applied after IV injection of the same amount of dextran in another group of mice. Dextran delivery outcomes were evaluated using fluorescence imaging of brain slices. The results showed that FUS+IN enhanced drug delivery within the targeted region compared with that achieved by IN only. Despite the fact that the IN route has limited drug absorption across the nasal mucosa, the delivery efficiency of FUS+IN was not significantly different from that of FUS+IV. As a new drug delivery platform, the FUS+IN technique is potentially useful for treating CNS diseases.[4]

Bibliography:

1. [1] Pourgholi F, Hajivalili M, Farhad JN, Kafil HS, Yousefi M. Nanoparticles: Novel vehicles in treatment of Glioblastoma. Biomed Pharmacother. 2016;77:98–107.
2. [2] Azad TD, Pan J, Connolly ID, Remington A, Wilson CM, Grant GA. Therapeutic strategies to improve drug delivery across the blood-brain barrier. Neurosurg Focus. 2015;38:E9.
3. [3] Meaghan A. O’Reilly, Kullervo Hynynen. (2012) Ultrasound enhanced drug delivery to the brain and central nervous system. International Journal of Hyperthermia 28:4, 386-396. Online publication date: 1-Jun-2012.
4. [4] Chen H, Chen CC, Acosta C, Wu S-Y, Sun T, Konofagou EE (2014) A New Brain Drug Delivery Strategy: Focused Ultrasound-Enhanced Intranasal Drug Delivery. PLoS ONE 9(10): e108880.
5. [5] Gutkin A, Cohen ZR, Peer D. Harnessing nanomedicine for therapeutic intervention in glioblastoma. Expert Opin Drug Deliv. 2016;13:1573–1582.
6. [6] Meng J, Agrahari V, Youm I. Advances in targeted drug delivery approaches for the central nervous system tumors: the inspiration of nanobiotechnology. J Neuroimmune Pharmacol. 2016 doi:10.1007/s11481-016-9698-1.
7. [7] Agrahari V, Agrahari V, Mitra AK. Nanocarrier fabrication and macromolecule drug delivery: challenges and opportunities. Ther Deliv. 2016a;7:257–278.
8. [8] Mangraviti A, Gullotti D, Tyler B, Brem H. Nanobiotechnology-based delivery strategies: New frontiers in brain tumor targeted therapies. J Control Release. 2016;240:443–453. 
9. [9] Pourgholi F, Hajivalili M, Farhad JN, Kafil HS, Yousefi M. Nanoparticles: Novel vehicles in treatment of Glioblastoma. Biomed Pharmacother. 2016;77:98–107.
   
10. https://www.cancerquest.org/patients/treatments/vaccines-treat-cancer#footnote1_568rtsw
11. http://bit.ly/2qwDOUk
12. https://www.cancer.gov/