Int J App Pharm, Vol 13, Issue 3, 2021, 39-46Review Article

NOSE-TO-BRAIN DELIVERY, A ROUTE OF CHOICE FOR TARGETING BRAIN TUMORS

IBRAHIM AMINU SHEHU1*, MOJAHIDUL ISLAM2, VIJENDER SINGH3

1School of Allied Health Science, Sharda University, Knowledge Park III 201306, Greater Noida, UP. India, 2School of Pharmaceutical Sciences, Lingayas Vidyapeeth University, Faridabad, India, 3Rakshpal Bahadur Pharmacy Institute, Plot No 04, Knowledge Park III 201306, Greater Noida, UP. India
*Email: ibrahimaminushehu@gmail.com

Received: 23 Dec 2020, Revised and Accepted: 13 Mar 2021

ABSTRACT

Brain tumours are the most lethal type of cancer, which is difficult to manage due to the inherent suboptimal bioavailability of the chemotherapy agent at tumour sites, consequent of high levels of protection of physiological blood-brain barrier (BBB), blood tumour barrier (BTB) and blood-cerebrospinal fluid barrier (CSF). Improving the permeability of these barriers would enhance the disease's clinical prognosis and promote patients' quality of life. To this end, scientists have conducted several studies to determine the most suitable route for CNS delivery. Most of which show that the nose-to-brain is proposed to be the most convenient, efficacious and clinically beneficial non-invasive means of delivering chemotherapeutic agents directly to the brain. Therefore, this study compares the therapeutic benefits of intranasal and other conventional brain delivery systems and further evaluates the clinical benefits of using different nanocarriers for brain tumour targeting. However, we surveyed the literature by conducting an in-depth search of the research keywords and their combinations in recognized scientific databases, primarily Science Direct, PubMed, Google Scholar, and Research Gate. Our findings have shown that the nose-to-brain delivery of chemotherapeutics is a breakthrough in bypassing the effects of BBB, BTB, and CSF barriers, improving the delivery of drugs to the brain for specific tumour targeting with desired clinical prognosis.

Keywords: Brain tumours, Glioblastoma, Intranasal route, Conventional delivery, Nanocarriers, Blood-brain barrier, and blood tumor barrier

© 2021 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijap.2021v13i3.40602. Journal homepage: https://innovareacademics.in/journals/index.php/ijap

INTRODUCTION

Edwin Smith was the first to discuss the central nervous system CNS's concept in his papyrus about 3,600 y ago [1, 2]. Later, about 1,300 BC, the Ebers’ papyrus described the concept of cancer and tumors [3]. Besides, Hippocrates identified some tumors in the crab’s legs and called them “karkinos,” in Greek words, meaning “crab/cancer,” in English [4]. The global brain cancer incidence is higher in men than in women, in developed than under-developed countries with the incidence and mortality rates of 3.4 and 2.5 par 100,000. Albania has the highest prevalence of 7.5 par 100,000 [5]. It accounts for 3% of all cancer globally [6]. Nevertheless, the significant risk factors are immune-imbalances, hormones, family history, smoking, alcoholism, in addition to radiation, and ageing [7].

Primarily, CNS tumors have been classified into; pituitary adenomas, gliomas, and primitive or vestibular neuroectodermal tumors, out of which ‘glioblastoma multiform’ (GBM) emerged as the most lethal type of CNS malignancy with 81% prevalence [8, 9] and 12–15 mo survival chance [10]. Moreover, the World Health Organization (WHO) graded the tumors into low-grade gliomas (grade I and II) and high-grade gliomas (grade III and IV), respectively [11]. Glioblastoma (high-grade glioma stage IV) is the most lethal type with less than a 5% survival rate [12], and more than 90% recurrence chances [13]. Nevertheless, the pattern of metastases and localization of glioblastoma malignancy remains unclear [14]. But, it shows dynamic changes in morphological and structural forms over time [15]. Understanding these concepts will significantly optimize the disease prognosis and increase the survival chances of the affected patients [16]. Henceforth, effective treatment of these malignancies is among the most challenging aspects of the pharmaceutical research field. Because, the blood-brain barrier (BBB), blood tumor barrier (BTB) and immunoregulatory mechanisms have become the rate-limiting steps for delivering chemotherapeutic agents to CNS [17]. The contemporary management approaches including surgery, radiation therapy [18]. and Temozolomide (TMZ) have shown limited clinical benefits [19]. Bypassing the BBB through an invasive approach (using physical carriers) could compromise brain functions and induce neurotoxicity. Therefore, a non-invasive (carrier-free) approach could increase drug permeability across the BBB to the target tumor [20]. Hence, the study of advances that could enhance drug delivery across these barriers is highly needed[21]. The established literature have proved the effectiveness of chemotherapeutic agents when delivered via the nose-to brain route through olfactory and trigeminal nerves [22]. The clinical benefits of using intranasal delivery outweigh that of other routes [23]. As we discussed in (table 3). However, the molecule meant for brain targeting should be highly lipophilic non-ionized, less than 400 Da molecular weight, with an ionization constant range from 0.5 to 6.0 at physiological PH [24]. Nonetheless, the aforementioned features alone are not enough to provide sufficient pharmacokinetic effects that could permit a molecule to cross BBB efficiently [25]. Although, mucociliary clearance, enzymatic degradation of proteins and peptides result in suboptimal bioavailability of such biomolecule in nasal delivery upon intranasal delivery [26, 27]. Perhaps, overcoming these hurdles will maximize the clinical benefit of the system. Nowadays, the potential technique for chemotherapeutic delivery enhancement for CNS tumor targeting is by encapsulating the drug into nanoparticles and administer them through the intranasal route [28, 29]. Nanoparticles have owed several advantages of optimization of drug pharmacokinetics to the compromisation of the physiological barriers enhancing the drug concentration at the targeted site [30]. Nevertheless, nano-size features of different NPs boost their transcellular transport proficiency, optimizing the targeted therapy for specified brain-tumors. Therefore, several NPs have been used as drug carrier vehicles for brain tumor targeting via nasal route [23, 31]. The review evaluates the clinical importance of brain tumor targeting through nasal administration and its therapeutic benefit over conventional delivery systems.

Brain tumors

Brain tumors have different classification types, most prominently; they have been classified into primary and secondary brain tumors [fig. 1].

Fig. 1: Classification of brain cancer

The primary tumors were categorized according to their originating tissues; gliomas, primitive, vestibular neuro-ectodermal, and pituitary adenoma. In contrast, the secondary tumors were characterized as metastatic tumors [32, 33]. The gliomas initiated from glial cells are the predominant types of CNS tumors that are associated with poor prognosis, including glioblastoma multiform (GBMs) which accounted for 81% of all brain tumors, astrocytoma (AS) oligodendrogliomas (OAs), among others. On the other hand, in 2004, the World Health Organization WHO further classified the CNS tumors based on their histopathological parameters using a four-point grading scale [ I-IV] [34] as illustrated in table 1.

Table 1: WHO grading of brain tumors

WHO Descriptive features Members Criteria Ref.
Grade I Slow proliferating non-malignant tumours, with high survival chances. angiocentric glioma, pilocytic astrocytoma, and subependymal giant cell astrocytoma Nil [35]
Grade II Slow proliferating tumours with a high-grade, recurrent tendency, they may be malignant or non-malignant. chordoid glioma of the third ventricle, low-grade diffuse astrocytoma, and cellular and clear cell ependymoma Cytological atypia (atypical cell)
Grade III Malignant tumours that might reoccur as a high-grade tumour anaplastic astrocytoma, and anaplastic oligoastrocytoma Mitotic and activity anaplasia
Grade IV Proliferate rapidly with high malignancy Glioblastoma multiform GBM Mitotic, activity anaplasia with necrosis, and microvascular proliferation

Rate limiting barriers for chemotherapeutic delivery to CNS

Both blood-brain and blood tumor barriers are known as inherent barriers that limit the absorption and transport of molecules between systemic circulation and the brain, which significantly reduces the bioavailability of pharmacological agents, reducing their clinical efficacy in treating various brain infections and disorders. As shown in [fig. 2].

Fig. 2: Blood-brain and blood-tumor barrier

The blood-brain barrier (BBB)

Anatomically, the BBB consists of an inner endothelial layer containing several tight junctions composed of claudin and occludin layers encapsulated with the basal membrane and further encircled by the Astrocyte. Pericyte is wrapped in the basal membrane between the outer Astrocyte and the endothelial layer. However, the tight junctions are solely responsible for limiting the paracellular movement of substances across BBB. Whereas the basement membrane augments its protective effectiveness [36–39] However, BBB is highly selective in nature, allowing only specific molecules with unique physiochemical properties of tiny size (preferably “nano form”), the molecular weight of less than 400 Da, ionization of 1.5 to 2.7 and intense hydrogen bonding. These features restrict the entrance of many drugs and bio-molecules into the brain [40-42].

Brain tumour barrier (BTB)

The brain tumour barrier is a protective layer formed consequent of an anatomical and physiological alteration of BBB, because of the regeneration of new blood vessels that oxygenate the growing tumour through the loosed-tight junctions of the endothelial cells. These newly formed vessels had some tiny pores that prevented the permeation molecules, including hydrophilic ones [43–45]. The affected tissue triggers the release of Vascular Endothelial Growth Factor (VEGF) that facilitated the neoangiogenesis system allowing the tumour to metastases throughout the brain. As a result, these changes further limited the absorption of chemotherapy agents’ into the targeted brain tumour [46].

Blood cerebrospinal fluid barrier (BCB)

Blood Cerebrospinal Fluid Barrier is the rate-limiting step for drugs and molecules absorption from the systemic circulation to CNS. Physiologically, the arrangement of choronoid plexus’ epithelium limits the molecular exchange from blood to CSF. Besides, the brain parenchymal cells formed an arachnoid membrane (double layer) between the pia and dura mater, guided by tight junctions that enhance the integrity of the BCB and serve as the drainage system of CSF. However, this barrier the second most preventive barrier after BBB that limits the drug permeation to CNS [47].

Mechanism of intranasal delivery of chemotherapeutic agents

Studying the anatomy and physiology of the nose and associated nerves are essential for understanding the nose-to-brain delivery mechanisms, useful for developing the ideal formulation for brain targeting [48, 49]. Conversely, the nasal cavity is divided by the lateral and septal walls into two halves, that supplies sensory and olfactory nerves; in which the olfactory nerves extend to the brain [50]. In contrast, the sensory innervation consists of the mandibular, maxillary, and ophthalmic zones of the trigeminal nerve [51]. The entire nose consists of three regions, namely the respiratory, olfactory, and vestibular areas [52] Extension of the olfactory nerve ends in the olfactory bulb (chemosensory zone) where the drug’s maximum concentration can be found in the brain. Interestingly, the olfactory bulb is directly connected to the brain, enabling the intraneuronal transport of a particular compound to different parts of the brain. Moreover, the olfactory mucosa supplies the skull in close vicinity to CNS [53]. Unfortunately, the molecules are delivered through an olfactory nerve in a delay pattern. Alternatively, the molecules infiltrate the pre-neural compartment of the cranial nerves and flow to the CSF, from where it permeates to different parts of the brain [54]. However, the trigeminal, olfactory and respiratory epithelia permit therapeutics to distribute to other brain sections. [55] S. Yadav et al. found the intranasal administration of cyclosporine A (CSA) nanoemulsion riches the brain at higher concentrations. It was identified to have reached the brain through the olfactory bulb, hindbrain, and midbrain (via olfactory epithelium) through CSF [56]. R. G. Thorne et al. investigated the rat’s CNS pathways involved in delivering insulin-like growth factor-1 (IGF-I) via intranasal route; the researchers identified the two significant ways through which administered insulin [125I] distributed and concentrated in the rats’ CNS and CSF. The “peripheral olfactory system” a system that links the nasal stream, olfactory bulbs, and anterior-brain portion. Whereas the “peripheral trigeminal system” channels nasal passage to brain steam and CSF. According to the authors’ report, intravenous administration of [125I] to another group revealed similar results with that of intranasal but showed lesser CNS concentration than an intranasal pathway [57]. Shinde et al. investigated the potential for nose-to-brain delivery of atomoxetine (ATX) encapsulated in liposomes using in vivo rat model experiments. Following a gamma scintigraphy examination, the result indicated a significant distribution of the drug in the CNS [58]. Therefore, good pharmacokinetics and physicochemical parameters of the drug determine its suitability for intranasal administration; usually, highly lipophilic unionized drugs that have low molecular weight are the desirable candidates for intranasal administration and hence could pass BBB through all these pathways [59]. As illustrated in [fig. 3].

Fig. 3: Mechanism of intranasal delivery of chemotherapeutics

Nanocarriers use for tumor targeting via a nose-to-brain delivery system

Nanocarriers transport the chemotherapeutic agents crossing BBB via several mechanisms, and they sustainably release the drugs to the brain. However, the FDA approved liposomes and dendrimers as a nanocarrier to deliver pharmacological agents to the brain. They have been widely used for targeting different types of brain disease through surface modification with other polymers and proteins [60, 30]. We summarized the literature of these in [table 2]

Preclinical studies

In vitro trials

Several studies have been carried out on the intranasal delivery of chemotherapeutics amongst Jeffrey J, et al.; demonstrated an in vitro experiment on rodents and primates models. The author examined the drug distribution in the rats’ perivascular space (PVS) and internal cerebral vessels using fluorescence imaging techniques, and the comparative study showed that the intranasal administration of the drug owed to have high distribution then intravenous administration. Therefore, the result indicated the potentiality of the intranasal route as an alternative way of delivering therapeutics for disease CNS targeting [61]. Khan A prepared and administered Temozolomide chitosan-nano-formulation using the Clone-6 (C6) glioma cell line of Wister rate via intranasal route. A histopathological examination at the end of the study has revealed the high delivery efficiency due to the mucosal effect from the chitosan-nanogel that sustained drug release. Moreover, the drug found to have attained the optimal concentration in the brain  [1]. Angel T. Alex, et al.; evaluated the permeation efficiency of the antineoplastic drug (carboplatin), the permeation of both Carboplatin-loaded nanoparticle (CP-NPs) and pure carboplatin formulation was determined using in situ, in vitro, and ex vivo evaluation studies. In an ex vivo study, the authors isolated the new mucosal cell line of sheep and tested the two formulations; the study indicated that the CP-NPs have higher permeation efficiency than the pure formulation. Likewise, the in vitro study was conducted using the CP-NPs formulations, one containing higher and the other holding a lower polymer concentration. After 72 h of administration to 96-growing human glioblastoma cells, the result indicated the rapid, followed by sustained release pattern in both formulations. Although the formulation that contained the lower polymer concentration has shown to release faster, this demonstrated the importance of using fewer polymers in such nano-formulations. However, the in situ evaluation has shown better nasal permeation in CP-NPs then the pure formulation. Overall, the Carboplatin-loaded nanoparticle (CP-NPs) could be a breakthrough for targeting brain tumors using intranasal administration [62]. Kanazawa, T., et al.; evaluated the safety and intranasal delivery efficiency of small interfering (siRNA) incorporated with modified block co-polymers-Tat nano micelles using rat modal. The in vitro study on glioma C6 cell-lines revealed high tumor inhibition upon intranasal delivery than intravenously injected formulation. Therefore, the author concluded that nose to brain rout is the most suitable means of targeting CNS disorders [63]. Maha N et al. formulated the intranasal Hyaluronic acid-based nanoemulsions of resveratrol and curcumin. The study shows the drug attained high concentration in the rats’ CNS due to the mucoadhesive nature and BBB permeation ability in the nasal passage [64]. Co-administration of acetazolamide with 5-fluorouracil via intranasal and intravenous routes was evaluated by Author links open overlay panel T. Shingaki, et al. The concomitant administration through nose-to-brain route was found to have enhanced the drug concentration to 104% and 46% against intravenous administration of 5-uracil alone [65]. The study conducted by Hee-Yeon, et al.; showed a significant increase in temozolomide’s anti-tumour activity (TMZ) after intranasal delivery to the rats bearing TMZ-resistant malignant gliomas. This means that temozolomide (TMZ) intranasal delivery could overcome the resistivity of oral TMZ-resistant malignant gliomas [66].

In vivo trials

J. H. Azambuja et al. administered siRNA-nanoemulsion intranasally to the Glioblastoma-induced Wister rats; the study’s result showed a 60% reduction of glioblastoma tumor on the tested rat [67]. T. Sakane et al., evaluated the perfusion of 5-fluorouracil (5FU) in the rats’ CSF using in vivo models of wister rats. The authors compared the intranasal and intravenous drug concentration in the CSF. The study result indicated that the drug’s high concentration reaches the CNS via CSF upon intranasal delivery than intravenous [65]. Luxiang, et al., conducted an in vivo evaluation of the efficiency of intranasal administration. The authors prepared and administered tyrosine kinase nanoparticles intranasally to glioma-induced rats. Upon examination, the study results indicated a maximum possible reduction in tumour size by facilitating the apoptosis rate, which is then observed in other preparation [68]. M. Colombo et al. evaluated the intranasal delivery of kaempferol-loaded nanoformulation and mucoadhesive nanosuspension using in vivo rat model. Histopathological investigation of the rats treated with both formulations has shown the significant reduction in the size of glioma cells. However, kaempferol nanoemulsion induced apoptosis largely than mucoadhesive nanosuspension [69]. E. Sekerdag, et al. compared the anti-glioma efficacy of 500 μM PEGlycated-farnesylthiosalicylic acid (FTA) on Wister rats for ten days intravenous and intranasal administration. After the post-treatment examination, the Nuclear Magnetic Resonance Imaging indicated the 55.7% reduction in tumor size. According to the study, there is no difference observed upon administering FTA via the intranasal or intravenous route. Matthias Van et al. encapsulated the small interfering RNA (siRNA) in chitosan nanoparticles and administered it into Glioblastoma-induced mouse intranasally. The author treated the mouse with the prepared formulation for days 5, 8, 12, and 15. However, the immunofluorescence test performed on the 5the day post-treatment showed a significant reduction in tumor size. The author further observed high concentration of drug in olfactory bulbus upon in vitro intranasal delivery via the olfactory pathway (from where the drug possibly distributes directly to the CNS) [70]. Darshana S. et al. administered both pure and Polylactic Acid (PLA) suspended nanoparticles of methotrexate via the intranasal route of two sub-grouped mice, each containing six members. The first group was treated with pure methotrexate has shown low bioavailability because the drug is highly hydrophilic in nature; consequently, it cannot cross BBB. On the other hand, the second group treated with PLA-methotrexate NPs has shown significant CNS concentration in both in vitro and in vivo evaluation after the pharmacokinetics evaluation. This is because the Polylactic Acid nanosuspension has the sol-gel-sol property that increases MTX’s mucosal residence time; hence, the BBB penetration and CNS distribution. Lastly, the cytotoxic evaluation has shown no difference in toxicity between both the study participants. However, the authors proposed thermosensitive nanoformulation to be a gold standard for the formulation of antineoplastic drugs intended to target CNS tumors through the nose-to-brain route. [71] A. Mangraviti, et al. have developed the polymeric nanoparticles incorporated with plasmid DNA to transfect “Human adipose-derived mesenchymal stem cells” (hAMSCs) through the intranasal route of glioma infected rats, as an alternative to viral transduction system. The in vitro evaluation revealed the significant reduction in glioma cells size more efficiently than the usual viral transduction method. While the in vivo experiment has indicated the possibility of high viability among the glioma bearing rats  [72]. Hiroyuki Taki, et al. evaluated the anti-tumour and safety effect of camptothecin (CPT)-nano-micelles on intranasal administration using glioma infected rats. The in vivo investigation revealed evidence of tumour-shrinking and high viability chances on the treated rats. The author established the safety of the formulation at a high dose of 2 mmol/ml [73]. According to the sun et al. report, the CNS concentration of Methotrexate (MTX) encapsulated in chitosan microspheres was determined to be 118% upon intranasal administration to healthy Wister rats. While it was remained undetected when administered intravenously. [74] The study conducted by Pineda JR, et al.; proved the effectiveness of intranasal infusion of Temozolomide (TMZ) as anti-glioblastoma in nude mice. After the drug administration 3times a week for two weeks, a remarkable reduction in tumor size without alteration in the mice’s sense of smell was observed [75].

Clinical studies for intranasal brain tumor targeting

DA Fonseca et al. performed a clinical evaluation for the effectiveness of intranasal administration of “perillyl alcohol” (POH) on 152, 26, and 5 different patients with a primary glioblastoma GBM, astrocytoma grade III AA and anaplastic oligodendroglioma AO, respectively. The drug was intranasally administered to the patients 4 times daily, initiating a minimal dose of 66.7 mg/dose, and titrated to 533.6 mg/day. The study outcome after 4 y of the study indicated a favourable prognosis among the tested patients. However, 19% of them have been clinically under remission. Although 95% of the patients have developed rare nasal bleeding and soreness [76]. C. Fonseca, et al. conducted a phase I/II clinical trial to access the safety profile of Perillyl alcohol (POH) on patients with relapsed malignant glioma. The author was administered the intranasal dose of 0.3% vol/vol containing 55 mg POH 4times daily and consecutively to 37 patients who had sub-grouped into 29 with Glioblastoma, 3 with anaplastic oligodendroglioma and 5 with astrocytoma grade III, for the period of 6 mo. Upon completing the cohort study, the preliminary result indicated the safety, reliability, and non-invasive anti-tumor efficacy of POH. Clovis Fonseca, et al., had performed a clinical analysis on 67 patients with brain tumors the study evaluated the effectiveness of intranasal chemotherapy with Perillyl alcohol (POH) among glioma patients. The relationship between tumor size, localization, and relative treatment prognosis has been observed. Throughout the study period, the patients were categorized into some groups, in which 52, 10, and 5 patients bearing GBM, AA, and OA were recruited, respectively. A daily dose of 440 mg POH was maintained among the recruited patients. The author observed the longer survival chances and the promising clinical prognosis among the patients bearing recurrent malignant glioma, while those having lobar localization and peritumoral oedema have shown poor prognosis and low survival chances. Therefore, the study indicated the safety and tolerability of non-invasive chemotherapy and evident the definite relationship between the tumor localization and clinical prognosis among glioma patients [78]. Clovis O. et al. the study on 62-year-old anaplastic oligodendroglioma patients revealed the notable reduction in tumor proliferation following the four times daily administration of l 0.3% POH intranasally [79]. However, the Brazil trial further affirmed the clinical safety, tolerance, and efficacy of intranasal POH, in a study that recruited 37 recurrent malignant glioma-bearing patients; these patients were treated with four times daily intranasal 0.3% POH for several days [80]. Chen TC et al. evaluated the safety and anti-tumor activity of POH in a clinical trial phase I/II among the patients with recurrent Glioblastoma. The patient has received 4-times daily intranasal POH for 6months; the trial evidenced the maximum shrinkage in the bearing patients’ tumor size with no toxicity and unwanted side effect [81]. Juliana et al. studied the clinical implication of POH's concomitant administration and ketotic diet among 32 patients with recurrent Glioblastoma. After four times daily intranasal administration of POH, 17 with ketotic and 15 without ketotic diet for a period of 3 month. Subsequent clinical investigation of the recruited patients, most of the patients who received the concomitant chemotherapy of POH with ketotic diet, shows significant tumor inhibition with no toxicity [82].

Table 2: Nanocarriers use for tumor targeting via the nose-to-brain delivery system

Nanoparticles Shape and size Mechanism of BBB circumvention Features Limitations Ref.
Liposomes Spherical, concentric, Size 50-100 μm Liposomes delivered the drug to the brain by permeating across the endothelial cells via endocytosis bi-layered, phospholipids that can entrap both hydrophilic and hydrophobic drugs and it possessed different surface charges Expensiveness, low drug loading capacity, and long term stability [83]
Solid lipid  spherical in shape 1 and 1000 nm It can permeate through the tight-junctions of the endothelium via a transcellular pathway and pass across the BBB High drug loading efficiency, control releasing overcome the effect of mucociliary clearance and nasal degradation High water content (70 to 99.9)%, Undesired drug load, leakage during storage [84]
Polymeric NPs

10-1000 nm

spherical or elongated

 Polymeric NPs lodges the chemotherapeutic drug in the brain through passive or active transportation Higher polydispersity index, stability, biocompatible biodegradable non-toxic, non-immunogenic and Inexpensive Clinical application is limited by uncertain toxicity [85]
Nanoemulsion globular size Improve mucosal absorption and overcome nasal mucociliary clearance Highly lipophilic, and permeation, low spherical size, Unavailability of intranasal product, [86]
Chitosan  3.2-3.5 µm in diameter The increase in temperature enhances the gel formation and positive charges of chitosan interact with the negative charge of the mucosa that results in excellent retention and paracellularly cross the tight junctions of epithelial cells of BBB Biodegradable, thermoresponsive, ease preparation, low toxicity, high stability and CNS delivery Poor aqueous solubility [87, 88]
Dendrimers three-dimensional structure of globular shape. The penetration efficiency of dendrimers potentiates by conjugation with transferrin, D-glucosamine, leptin, and lactoferrin. The release depends on the PH and ionic strength of the media. Undergo compositional changes in response to the environmental condition, wide therapeutic applications Extremely low water-soluble [89]

CONCLUSION

It is no gainsaying that brain cancer is a severe disease characterized by an inferior clinical prognosis. There are overall limited survival chances for brain cancer patients perhaps;, the patients bearing Glioblastoma multiform (GBM) are more clinically affected since their survival chances are no longer than 15 mo. Nevertheless, the optimum concentration of active drugs at the brain’s targeted site is a prerequisite for effectively managing the disease or disorder. Unfortunately, several anatomical and physiological barriers need to be overcome before the therapeutic agent could reach the brain. Most importantly, blood-brain (BBB), blood tumor barriers (BTB), and blood-cerebrospinal fluid barrier BCB. The choice of the suitable route of administering such drugs became very challenging; the oral, intravenous, and intrathecal routes have failed to provide the desired bioavailability. However, the non-invasive course for delivering chemotherapeutics to the brain to target various CNS tumors needs to be studied. The nose-to brain delivery was an alternative route for delivering anticancer drugs to CNS, being non-invasive and highly efficient in bypassing the blood-brain and brain tumor barriers while limiting the systemic side effects.

Although the intranasal delivery mechanism is not well understood, several investigations have demonstrated the drug to have reached the brain mainly through the olfactory and trigeminal nerves. However, incorporating nanoparticle and materials in the drug formulations has further enhanced the drug permeation across the BBB via the nose-to-brain route. Nevertheless, an extensive study on brain tumor targeting via the nose to brain rout will provide sufficient knowledge to aid the drug development and therapeutic outcomes of devastating brain tumors and other disorders. Therefore, nose-to-brain delivery of chemotherapeutics serves as the breakthrough for bypassing the effect of BBB, BTB, and CSF barriers. For that reason, designing the chemotherapeutics agents in the form of inhalational nanoformulation will enhance the clinical prognosis of CNS tumors and the patients’ quality of life.

ACKNOWLEDGEMENT

I acknowledged my parent, teachers, and colleagues’ effect forgiven me unflinching support and guidance in my personal and academic affairs.

FUNDING

Nil

AUTHORS CONTRIBUTIONS

All the authors have contributed equally.

CONFLICT OF INTERESTS

The author declared nil conflict of interest

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