Journal of Neuro-Oncology

, Volume 116, Issue 3, pp 437–446

A systematic review of inhaled intranasal therapy for central nervous system neoplasms: an emerging therapeutic option

Authors

    • Department of Neurosurgery, Keck School of MedicineLos Angeles County-USC Medical Center
  • Amy Bansal
    • Department of Neurosurgery, Keck School of MedicineLos Angeles County-USC Medical Center
  • Florence Hofman
    • Department of Neurosurgery, Keck School of MedicineLos Angeles County-USC Medical Center
  • Thomas C. Chen
    • Department of Neurosurgery, Keck School of MedicineLos Angeles County-USC Medical Center
  • Gabriel Zada
    • Department of Neurosurgery, Keck School of MedicineLos Angeles County-USC Medical Center
Topic Review

DOI: 10.1007/s11060-013-1346-5

Cite this article as:
Peterson, A., Bansal, A., Hofman, F. et al. J Neurooncol (2014) 116: 437. doi:10.1007/s11060-013-1346-5

Abstract

The intranasal route for drug delivery is rapidly evolving as a viable means for treating selected central nervous system (CNS) conditions. We aimed to identify studies pertaining to the application of intranasal drug administration for the treatment of primary CNS tumors. A systematic literature review was conducted to identify all studies published in the English language pertaining to intranasal therapy for CNS neoplasms, and/or general mechanisms and pharmacokinetics regarding targeted intranasal CNS drug delivery. A total of 194 abstracts were identified and screened. Thirty-seven studies met inclusion criteria. Of these, 21 focused on intranasal treatment of specific primary CNS tumors, including gliomas (11), meningiomas (1), and pituitary adenomas (4). An additional 16 studies focused on general mechanisms of intranasal therapy and drug delivery to the CNS using copolymer micelles, viral vectors, and nanoparticles. Inhaled compounds/substances investigated included perillyl alcohol, vesicular stomatitis virus, parvovirus, telomerase inhibitors, neural stem and progenitor cells, antimetabolites, somatostatin analogues, and dopamine agonists. Radiolabeling, CSF concentration measurement, imaging studies, and histological examination were utilized to clarify the mechanism and distribution by which drugs were delivered to the CNS. Successful drug delivery and tumor/symptom response was reported in all 21 tumor-specific studies. The intranasal route holds tremendous potential as a viable option for drug delivery for CNS neoplasms. A variety of antitumoral agents may be delivered via this route, thereby potentially offering a more direct delivery approach and ameliorating the adverse effects associated with systemic drug delivery.

Keywords

CNS tumorNeoplasmInhalantIntranasalChemotherapyPharmacokinetics

Introduction

Central nervous system (CNS) tumors present a unique therapeutic challenge, largely resulting from low permeability of the blood brain barrier (BBB) to most chemotherapeutic agents [1]. Due to toxicities associated with intravenous, oral, and intrathecal chemotherapy agents for primary CNS neoplasms, numerous investigators have realized the potential of intranasal drug administration to treat CNS tumors. Intranasal drug delivery is a noninvasive and practical alternative to other forms of chemotherapy, and facilitates frequent patient self-administration in a pain-free, noninvasive manner. Due to numerous anatomical communications between the CNS and nasal mucosa, including the olfactory and trigeminal nerves, intranasal drug delivery may theoretically bypass the BBB and avoid hepatic first-pass drug metabolism [2]. Because inhaled drugs are not administered systemically, complications associated with systemic drug delivery are theoretically minimized.

Intranasal therapy for primary CNS disease, however, has yet to effectively translate to clinical practice, and remains limited to preclinical studies and small early-phase clinical trials. To summarize preexisting research regarding intranasal therapy for CNS tumors, we performed a systematic literature review, and gathered mechanistic studies pertaining to intranasal drug delivery for targeting brain tumors, focusing on tumor subtype, experimental models, drugs classes, pharmacokinetics, toxicity, and clinical outcomes.

Materials and methods

Search parameters

A systematic literature review was performed to identify studies regarding inhalational/intranasal therapy for CNS tumors. PubMed, Google Scholar, and Web of Knowledge databases were utilized to identify studies published in the English literature between 1989 and 2013. Searches included the following terms: intranasal, inhalant, therapy, treatment, drug, administration, CNS tumor, brain tumor, astrocytoma, glioblastoma multiforme (GBM), pituitary, tumor, glioma, meningioma, skull base. A primary abstract review (n = 194) was performed for all articles meeting initial search criteria. References of all relevant articles were additionally searched.

Inclusion criteria

Two major inclusion criteria were used; firstly, studies reporting the use of intranasal/inhalant therapy in the treatment of any CNS tumor were included. Secondly, studies pertaining to general mechanisms of intranasal drug delivery and pharmacokinetics were included. Both human (clinical) and animal (preclinical) experimental studies were included, as were clinical reviews. Due to the heterogeneity of standard controls and primary outcomes across studies, statistical meta-analysis was not performed. Outcome data extracted from primary manuscripts included tumor type (pathology), details of animal/clinical model, drug type, mechanism of action, dose/frequency of drug administration, pharmacokinetics, efficacy, and adverse effects.

Results

An initial database search produced 194 abstracts that underwent primary review (Fig. 1). Of these, 37 studies met inclusion criteria and underwent final full-text review. Included studies were subsequently classified as general targeting/mechanism studies (n = 16) or inhalant treatment for CNS neoplasms (n = 21). Treatment articles were subsequently classified according to tumor pathology and drug compounds tested (Table 1).
https://static-content.springer.com/image/art%3A10.1007%2Fs11060-013-1346-5/MediaObjects/11060_2013_1346_Fig1_HTML.gif
Fig. 1

Flow chart of systematic database review results

Table 1

Summary of papers which met inclusion criteria following review

Study

Medication

Dosage frequency/amt

Tumor type

Human/animal

Results

Da Fonseca et al. [20]

POH

4× daily/Pt. specific dose escalation

GBM

Human

POH has preventive and therapeutic effects in tumor models; POH inhibits posttranslational isoprenylation of Ras

Da Fonseca et al. [24]

POH

0.3 % v/v (55 mg) 4× daily/220 mg/day total

GBM

Human

Decreased tumor size, recovery of left hemiparesis and bladder incontinence

Da Fonseca et al. [23]

POH

0.3 % v/v (55 mg) 4× daily/220 mg/day total

GBM

Human

Some tumor size regression, non-toxic

Da Fonseca et al. [26] (Phase I/II Study)

POH

0.3 % v/v (55 mg) 4× daily/220 mg/day total

GBM

Human

Well tolerated treatment, improvement in tumor response rates suggested

Da Fonseca et al. [25]

POH

Daily/440 mg

GBM

Human

Reduction of tumor size and peritumoral brain edema (PTBE) in patients with good therapeutic response

Da Fonseca (2010)

POH

0.3 % v/v (55 mg) 4× daily/220 mg/day total

GBM

Human

Increased overall survival of patients with recurrent GBM

Hashizume et al. [36]

GRN163

6 μl PBS containing 0.65 μl/65 μl GRN163 every 2 min over a 22 min period (alternating nostrils)/65 μl total

GBM

Rat

FITC-labeled GRN163 accumulated in tumor cells and prolonged rat survival time, inhibiting tumor growth

Kiprianov et al. [34]

H-1PV

1 dose, 7 days after glioma inoculation/108 pfu of H-1PV in 100 ml PBS, 50 ml in each nostril

GBM

Rat

Tumor regression and prolonged rat survival time in both rats with rat glioma and immunodeficient rats infected with human glioma cells

Ozduman et al. [31]

VSV

1 dose, 4 days after glioma inoculation/25 μl solution containing 2.5 × 107 PFU of VSVrp30a in each nostril

GBM

Mouse

Infection of tumor cells and subsequent lysis, minimal toxicity versus normal brain cells

Reitz et al. [15]

NSPC

1 dose/8 μl total, 4 μl per nostril

GBM

Mouse

NSPCs targeted tumor regions and gathered there

Wollman et al. [30]

VSV

1 dose given to day 16 mice/25 μl phosphate-buffered saline (PBS) containing 107 PFU of VSVp1–GFP in each nostril

GBM

Mouse

3 groups of virus variants attained different results, the desired combination of minimal toxicity and sufficient oncolysis resulted from VSV-M51, VSV-CT9-M51, VSV-p1-GFP, and VSV-p1-RFP

van Seters et al. [42]

Buserelin

4× daily for 12 months/300 μg/dose for 1,200 μg total per day

Meningioma

Human

Maintenance of tumor symptoms (headache, visual disturbances, etc.), no regression of tumor size

Invitti et al. [44]

Octreotide

0.125 mg tid, doubling the dosage up to 2 mg tid

Pituitary Adenoma

Human

Marked decrease of GH and tolerated well with only mild side effects

Loh et al. [47]

Desmopressin

2× daily/0.1 ml

Pituitary Adenoma

Human

Effective treatment of post-operative symptoms of diabetes insipidus s/p resection of intra- and suprasellar lesions

Sharma et al. [46]

Octreotide

4 single doses, randomly administered/500, 1,000, 2,000 μg intranasal (100 μg sc as well)

Pituitary Adenoma

Human

GH suppression soon after application of drug, rate of absorption faster for intranasal administration versus subcutaneou

Weeke et al. [43]

Cabergoline

1 dose/10 μl each nostril of 0.045 ± 0.002 mg/kg body weight

Pituitary Adenoma

Rat

Intranasal mucoadhesive microemulsion is stable, effective, and efficient against PA

Sakane et al. [37]

5-Fluorouracil

1 ml/min flow rate of 50 uCi/ml solution

General

Rat

Intranasal perfusion administration of drug resulted in a much larger CSF uptake clearance versus instravenous route (8.65 vs. 6.20 ul/min/g tissue)

Shingaki et al. [39]

Methotrexate

1 dose/1,850 kBq (3.3 nmol) in 50 μl saline containing 1 w/v % CMC, 25 μl bilaterally. Repeated experiments for certain rats 2× or 3×, as well

General

Rat

Inhibitory effect on in vitro 9L glioma cells, reduced tumor weight versus control and IP groups, direct transport to CSF and brain confirmed via pharmacokinetic studies

Shingaki et al. [38]

Methotrexate (MTX), cisplatin analogue pyridoxatodiammineplatinum (II) (P-PtB), and mitomycin C(MMC)

4 doses/

General

Rat

MTX reduced tumor weight, P-Ptb and MMC did not - intranasal application of drug can be an effective novel approach for treatment

Wang et al. [40]

Methotrexate

/3.2 mg/kg

General

Rat

Intranasal administration resulted in higher CSF concentration and lower plasma concentration of drug versus IV administration

Wang et al. [41]

Raltitrexed

1 dose 30 min post operation/2.5 mg/kg

General

Rat

Raltitrexed had a much lower plasma concentration and longer constitution in the brain s/p intranasal administration as opposed to IV administration

Born et al. [12]

Neuropeptides

1 dose/10 mg MSH/ACTH (4–10) or 80/40 IU vasopressin or 40 IU insulin

Mechanism

Human

Intranasal administration of each peptide resulted in an elevation of its concentration in the CSF validating the i.n. route for peptide administration

Chen et al. [17]

Solanum tuberosum lectin nanoparticles

1 dose/0.5 mg in 20 μl buffer

Mechanism

Rat

enhanced brain delivery by STL-NP with lower exposure in circulation

Dhuria et al. [8]

n/a

n/a

Mechanism

n/a

A review focusing on current mechanistic understanding and discussion backing the olfactory nerve pathway as the major intranasal route for drug administration to the CNS

Fehm et al. [13]

Neuropeptides

n/a

Mechanism

Human

Neuropeptides are rapidly transported into CSF compartment, gaining access in CNS receptors

Fliedner et al. [11]

Radioiodinated leptin

1 dose alternating droplets between nares/24 μl [125I] leptin

Mechanism

Rat

Demonstrated a direct transport from nose to brain by circumvention of the blood–brain barrier by radioiodinated leptin

Frey et al. [9]

Iodinated 125I-NGF

1 dose over 30–40 min, 6 μl drops to each nare/50 μl125I-NGF

Mechanism

Rat

Concentration of iodinated NGF in the olfactory bulb follow intranasal administration suggests direct nose to brain delivery

Illum [3]

n/a

n/a

Mechanism

n/a

Intranasal administration of medication is an effective treatment method for many illnesses and will become more popular

Illum et al. [4]

n/a

n/a

Mechanism

n/a

An olfactory pathway for drug administration is not only a possibility but a reality in humans

Jansson et al. [18]

Fluoroscein Dextran

1 dose in the right nostril/50 μl FD3 in saline

Mechanism

Rat

Once FD3 is absorbed transcellularly across the rat olfactory epithelium, it is directly transferred to the olfactory bulb

Kanazawa et al. [19]

Tat analog-modified methoxy poly(ethylene glycol) (MPEG)/poly(ε-caprolactone) (PCL) - MPEG-PCL & MPEG-PCL-Tat

1 dose/50 μl of micelle suspension

Mechanism

Rat

both compounds formed nanoparticles with Tat on the surface, smaller particles penetrate mucosal layer better and reach the brain, MPEG-PCL-Tat showed much greater brain distribution, potential side effects

Lochhead and Thorne [1]

n/a

n/a

Mechanism

n/a

Olfactory nerve route is the major proponent of delivering drug along the intranasal route; trigeminal nerves, vasculature, and lymphatics play a lesser role

Lundstrom et al. [14]

Alphavirues

Unavailable

Mechanism

Mouse

Alphavirus can successfully be delivered to the CNS by intranasal administration of replication-competent virus; Alphaviruses have a broad host range but can be targeted by introducing binding-domains into the SIN envelope protein E2

Mistry et al. [6]

Nanoparticle Loading of Medication

n/a

Mechanism

n/a

Direct nose-to-brain transport using synthetic nanoparticles is possible in animal and human models, though many questions still remain

Talegaonkar et al. [5]

n/a

n/a

Mechanism

n/a

The rapid, non-invasive effects of intranasal administration of medical therapy are considerable advantages, especially given the efficacy and lack of systemic side effects

Thorne et al. [7]

Wheat germ agglutinin-horseradish peroxidase (WGA-HRP)

Single droplets to each nare over 15–30 min periods/25–50/zl of 1 % WGA-HRP or 1 % HRP

Mechanism

Rat

WGA-HRP was detected in the olfactory bulb following i.n. administration demonstrating the capacity of the olfactory route

Thorne et al. [10]

Insulin-like growth factor-I (IGF-I)

6–8 l drops, alternating between each naris every 2–3 min, over a total of 18.5 min/50 μl total

Mechanism

Rat

Intranasally delivered IGF-I can bypass the blood–brain barrier via olfactory- and trigeminal-associated extracellular pathways to rapidly elicit biological effects at multiple sites within the brain and spinal cord

Pharmacokinetics of inhaled intranasal therapies

Limited data exists regarding the general pharmacokinetics of intranasal therapy, with 16 identified studies implicating a variety of routes by which various agents may reach the CNS following intranasal delivery [1, 38]. Radiolabeling [911], CSF concentration measurements [12, 13], imaging studies, and histological examination [14, 15] have been used to elucidate the route(s) and mechanism(s) by which intranasal compounds are delivered into the CNS.

A brief summary of nasal anatomy is helpful in understanding the mechanism of intranasal therapy (Fig. 2). The nasal cavity consists of three regions—vestibule, respiratory region, and olfactory region. The vestibule comprises the most anterior of these regions and is covered with stratified squamous epithelium. Respiratory epithelium is characterized by its large surface area where systemic vascular absorption occurs [4]. The olfactory region comprises just 3–5 % of total nasal cavity surface area [4], yet is the most important anatomical region pertaining to intranasal drug administration. Because olfactory mucosa lies in the superior nasal cavity directly inferior to the cribriform plate, above normal airflow pathways, odorants reach these receptors by diffusion, representing one of few direct communications between the CNS and external environment. Olfactory epithelium contains sensory neurons, whose axons penetrate the epithelial layer to join additional axons and form bundles in the underlying lamina propria. These axons cross the cribriform plate to enter the cranial cavity and synapse in the olfactory bulb [4].
https://static-content.springer.com/image/art%3A10.1007%2Fs11060-013-1346-5/MediaObjects/11060_2013_1346_Fig2_HTML.gif
Fig. 2

Schematic of pertinent nasal anatomy for inhalant therapy. Image courtesy of Anatomical Justice

The unique anatomical relationships between the nasal cavity and CNS provide a direct delivery route, by passing through olfactory (and possibly trigeminal) nerves connecting the nasal/sinus mucosa and CNS. When substances contact olfactory nasal mucosa, they can be rapidly transported into the CNS [1]. The BBB is theoretically bypassed, thereby facilitating delivery of larger molecules, peptides, proteins, and viral vectors which are otherwise inhibited from entering the CNS. As a result, lower requirements for drug administration are feasible, as hepatic first-pass metabolism and the destructive effects of gastric acid are obviated [5]. For stem cells, which can cross the BBB and enter the brain [16], delivery through the nasal route would allow for repeated treatments versus other potentially more invasive transplantation methods [15]. Increased efficiency due to lower drug administration requirements also holds true for intranasal stem cell delivery as compared to other routes of treatment.

Two mechanisms have been implicated in drug transport from the olfactory region into the CNS: the axonal and olfactory-epithelial pathways. The axonal pathway involves intracellular absorption of compounds by primary olfactory epithelium neurons, and subsequent migration along axonal transport systems. Olfactory neurons can also endocytose albumin, certain viruses, and other compounds, potentially serving as drug carriers or chaperones [1]. Although this pathway involves slower transport compared to olfactory epithelial pathways, it also facilitates drug delivery to more distant CNS regions [3, 4].

Autoradiography, histological sections, MRI studies, and fluorescent microscopy demonstrate concentration of intranasal-delivered substances at the olfactory bulb. Using high-resolution phosphor imaging of CNS sections after intranasal treatment with 125I-IGF-I in rats, signal intensities peaked in the olfactory bulb on autoradiograms [10]. Another study testing intranasal administration of superparamagnetic iron oxide particle-tagged neural stem/progenitor cells (NSPCs) for gliomas via MRI in vivo tracking showed a frontal distribution pattern also supporting olfactory region targeting [15]. Similarly, NSPCs tagged with green fluorescent protein for histological examination showed migration along olfactory nerve pathways following intranasal application [15]. Finally, coumarin-filled nanoparticles modified with glycoproteins were viewed with fluorescent microscopy and demonstrated rapid uptake in the olfactory bulb and brainstem, implicating both olfactory and trigeminal nerve routes [17].

By crossing epithelial cell junctions, drugs may enter the lamina propria via transcellular or paracellular routes [4]. Once in the lamina propria, substances may be absorbed by perivascular, perineural, or lymphatic channels [10]. Most substances that rapidly enter the CNS do so via perineural routes, but how compounds reach the brain from the perineural space is not completely understood. Based on known kinetics of axonal transport, extracellular diffusion, and extracellular convection, the most likely mechanism mediating rapid uptake is extracellular bulk flow along olfactory and trigeminal nerve channels [1]. Extracellular bulk flow is a relatively rapid process, and the uptake of intranasal drugs into the CSF and CNS typically occurs within minutes [4].

Studies using radiolabeled nerve growth factor (NGF) in rats demonstrated dramatic increases in the CNS following intranasal administration, but not intravenous administration, supporting direct bypass of the BBB [9]. The rapid rise of NGF seen 20-60 min following intranasal administration supports paracellular uptake pathways through olfactory epithelium, rather than slower intracellular transport processes [9]. Additional studies tracking the distributions of inhaled leptin [11], IGF-1 [10], and vascular endothelial growth factor [1] also showed peak CNS concentrations 20–60 min post-treatment. In a study sampling CSF and serum for various peptides (melonocortin, vasopressin, insulin) in human subjects 80 min following intranasal administration, CSF concentrations increased following administration. In the case of melanocortin and insulin, no concomitant increases in serum concentrations were noted, supporting a direct nasal to CNS transport route. Furthermore, CSF concentrations of melanocortin increased as early as 10 min following administration, suggesting rapid drug migration via paracellular routes [12]. Finally, inhaled fluorescent-labeled dextran was seen gathered around olfactory nerve bundles several minutes after intranasal administration, also supporting the theory of transcellular drug delivery routes [18]. Investigation is underway to improve targeting and delivery of intranasal therapies. For example, Kanazawa et al. [19] used amphilic copolymer, methoxy poly(ethylene glycol)/poly ε-caprolactone) (MPEG-PCL), and Tat-modified MPEG-PCL loaded with coumarin to enhance CNS uptake via intranasal delivery. Using fluorescence microscopy, they noted that Tat-modified copolymers showed more robust distribution patterns in treated rats.

Tumor-specific treatment using intranasal therapy

Astrocytoma/glioma

A majority of inhalational studies (n = 11) for primary CNS tumors have focused on GBM, the most common primary malignant brain tumor. The aggressive and infiltrative nature of GBM often limits the therapeutic potential of surgical intervention, radiation therapy and chemotherapy. Ras, a signaling protein downstream of EGFR and PDGFR tyrosine kinases, is over-expressed in human GBM cell lines [20]. Several experimental drugs for GBM intervene along the Ras pathway in an attempt to ameliorate the rapid growth patterns associated with GBM. One example is Perillyl alcohol (POH), a naturally-occurring limonene compound with anti-neoplastic properties. POH suppresses Ras protein activity and interferes with vital cell functions [20]. Treatment with POH results in perturbations in cell morphology, decreased viability, and apoptotic death in primary human GBM cell cultures [21]. Although oral POH administration has been studied for late-stage systemic cancers, it was associated with severe gastrointestinal toxicity [22].

Numerous early-phase studies have tested the safety and efficacy of intranasal aerosolized POH, which has been tolerated with no reported major toxicities [2327]. A recent Phase I/II clinical trial examined outcomes of intranasal POH in patients with refractory high-grade gliomas [26]. At 6-month follow-up, 48.2 % of GBM patients achieved progression-free survival [26]. Tumor volume reduction and facilitation of corticosteroid discontinuation were seen in two patients. Despite these observations, no patients receiving intranasal POH showed reduction in peritumoral edema on MRI [26]. Another study investigated the effects of intranasal POH for recurrent GBM with escalating doses of POH. Patients receiving POH treatment had longer mean survival (5.9 months) compared to control participants (2.3 months) receiving current conventional multimodal therapies [27]. Finally, in vivo experiments show that intranasal POH can decrease the growth of implanted temozolomide-resistant glioma cells [28].

Another approach to inhalant treatment for CNS neoplasms involves viral delivery. Although several viruses show glioma specificity, an inherent challenge associated with oncolytic viruses is risk posed to normal tissue, which is particularly consequential in the CNS because neuronal tissue does not normally regenerate. Vesicular stomatitis virus (VSV), however, has known proclivity for tumor cells, likely due to their aberrant interferon signaling [29]. One in vitro study showed that several VSV variants demonstrate increased activity against GBMs, in addition to attenuated virulence against normal brain tissue [30]. In vitro experiments showed greater VSV binding and internalization in glioma cells compared to normal astrocytes [31]. Ozduman et al. [31] tested intranasal VSV in mice transplanted with red fluorescent protein-modified U87 glioma cells. Following transplantation, VSV infection was noted within the tumor but not surrounding brain. The authors later investigated how intranasal VSV could affect peripherally placed sentinel tumors, and found no viral infection at remote sites, suggesting that intracranial delivery is mediated by neural and not systemic/vascular pathways.

Parvovirus H-1PV is another virus studied for intranasal treatment of CNS tumors, and has shown preclinical efficacy against malignant tumors when administered intracranially or intravenously [32]. Given that lytic viral replication requires the host cell be in a poorly differentiated state, the use of these viruses against tumors may be opportune [33]. In one study, rats implanted with rat or human GBM cells were given intranasal H-1PV 7 days later [34]. Intranasal H-1PV led to complete tumor remission in immunocompetent rats implanted with rat GBM cells, and immunodeficient rats implanted with human GBM cells survived one week longer than controls. Analyzed tissue samples showed viral DNA dispersed throughout the brain, with predominant accumulation in the tumor region. Immunohistochemistry showed that viral cytotoxic proteins (i.e. NS-1) were seen exclusively in tumor cell regions 5 days following intranasal therapy. However, transient viremia and viral DNA in the liver and spleen of sacrificed animals was detected, suggesting potential systemic effects.

Targeted gene therapy represents another possible treatment strategy for GBMs, and may reduce effects on normal tissue. For instance, gliomas express telomerase whereas normal brain cells do not [35]. GRN163, a 12-m oligonucleotide N3′− >P5′ thiophosphoramidate telomerase inhibitor, is effective when injected intratumorally in athymic rats with subcutaneous and intracerebral human GBM xenografts [22]. To investigate the effectiveness of intranasal administration, GRN163 was administered to rats with CNS-implanted U-251 MG human GBM cells [36]. Drug distribution was assessed using fluorescence microscopy, and showed visible compound at the tumor site 4 h following administration, with little to no fluorescence in normal brain cells. Average survival in treated rats was 75.5 days compared to 36 days in controls. In three treated rats, no toxicity or behavioral/neurological deficits was seen 104 days post-treatment, and histology showed no tumor at the original implantation site.

Another promising avenue is intranasal delivery of NSPCs. Although previously used to treat gliomas, NSPCs required surgical implantation, thereby limiting their potential as a chronic therapy. In one study, mice injected with orthotopic GBM xenografts were treated with intranasal NSPCs and compared to controls [15]. Histopathologic samples showed localization of NSPCs at primary and satellite tumor sites 5 days after intranasal therapy, whereas no NSPCs were detected in controls. Serial MRI and histologic confirmation showed peak NSPC density at the tumor site 24 h following treatment, and that most NSPCs migrated via olfactory nerve/bulb pathways. These results suggest that NSPCs show direct tumor tropism, which may lend itself to noninvasive delivery via intranasal application. Systemic tissue samples, however, showed scattered NSPCs in the spleen following intranasal therapy.

Non-specific treatments

5-Fluorouracil [37], methotrexate [3840], and raltitrexed [41] are anti-metabolites used for cancer treatment. Although 5-fluorouracil and raltitrexed are commonly administered intravenously, methotrexate is given orally. Recently these drugs have also shown efficacy in treating brain cancer when administered intranasally in rat models. However, the risk of toxicity was high in these studies, as these drugs do not sufficiently discriminate between tumor and normal brain tissue [36].

Meningioma

Meningiomas are the most common primary brain tumors, and often arise along the anterior/middle skull base in direct proximity to the paranasal sinuses, making them potentially ideal targets for intranasal delivery. Furthermore, meningiomas invading the cavernous sinus may be suitable targets for intranasal therapy because of the course of the trigeminal nerve and venous drainage from the paranasal sinuses. Because meningioma tumorigenesis and progression is partially driven by hormonal factors (i.e. progesterone receptor expression), various hormonal agents have been used to treat refractory meningiomas. In one case report, a patient with refractory meningioma was treated with the LHRH superagonist buserelin, administered intranasally [42]. Chronic intranasal buserelin treatment alleviated the patient’s headaches, but failed to induce tumor regression. Following treatment withdrawal, the patient experienced recurrence of headaches, decreased vision, diplopia, and trochlear nerve paresis.

Pituitary adenoma

Pituitary adenomas also arise in direct proximity to the sphenoid sinus, and may therefore be ideal tumor candidates for intranasal therapy. Depending on the subtype, various agents are used to treat functional pituitary adenomas causing acromegaly, Cushing’s Disease, and hyperprolactinemia. In one study, intranasal administration of the somatostatin analogue octreotide in acromegaly patients resulted in twofold increases in absorption and duration of effect, compared to subcutaneous administration [43]. Another study monitored 8 acromegaly patients who used octreotide nasal powder, and reported a decrease in growth hormone levels with only mild side effects [44]. Improved intranasal octreotide uptake was also seen when administered via an iontophoretic delivery system [45]. Prolactinomas are primarily treated with dopamine agonists (i.e. bromocriptine and cabergoline). In albino rats treated with intranasal cabergoline, an increase of half-life in the brain, drug targeting efficiency, and proportion of direct drug transport to the brain was seen, versus intravenous and oral routes. Furthermore, no apparent toxicity was reported [46]. Intranasal desmopressin has also long been used to treat diabetes insipidus following surgical resection of intra- and suprasellar lesions [47]. It remains unclear, however, to what extent these effects are caused by direct tumor delivery versus improved vascular absorption.

Limitations and future implications

Mounting evidence supports the use of inhalant therapies for CNS neoplasms. Preclinical animal models have supported the feasibility of this delivery system as a non-invasive means of potentially treating refractory tumors. Limitations of this technique include relatively low absorption rates across the nasal epithelium, which may limit delivery of highly potent substances. Some evidence suggests that only a small fraction of drug reaches the CNS directly via the intranasal route. This is due in part to several factors including the low permeability of the nasal mucosa to polar molecules, the smaller relative proportion of olfactory region mucosa in humans compared to other animals, rapid clearance of administered drugs by the mucociliary clearance mechanism, and possible enzymatic degradation within the nasal cavity or across the epithelial barrier [3]. These hurdles could potentially be overcome with development of improved aerosol, drug- copolymer micelle, viral vector, and/or nanoparticle delivery systems [4].

The current review is inherently limited by several critical factors, including the potential for publication bias. With regard to generalizability, a majority of research has been conducted in animal models, with very little clinical data aggregated regarding use of these inhalant therapies in human subjects. Despite these limitations, these studies lend support to the idea that intranasal therapy is an optimal strategy for treating patients with refractory CNS tumors suffering from toxicities incurred from systemic treatments. Further investigation into the safety and efficacy of drugs delivered intranasally is required to better understand their role in treating CNS neoplasms. In the future, harnessing the potential of intranasal delivery of anti-tumoral agents may reduce or obviate the need for surgery, radiation and toxicities associated with systemic chemotherapy.

Conclusions

Intranasal delivery of antitumoral agents for CNS neoplasms is a promising alternative to systemic chemotherapy. Several small successes regarding intranasal delivery in the treatment of CNS neoplasms have been achieved, including the use of POH and the virus H-1PV for gliomas. Larger prospective clinical trials are underway to validate early findings and further define the clinical role of intranasal drug delivery systems.

Conflict of interest

We declare that we have no conflict of interest.

Copyright information

© Springer Science+Business Media New York 2014