Name: Stereotactic Intracranial Implantation of Glioblastoma Patient-derived Xenograft Cell Lines in Mice (Video) | JoVE Journal
Uploaded: 2026-02-27T13:25:00.000+00:00
Duration: 8 min 24 s
Description: Learn stereotactic intracranial implantation of glioblastoma patient-derived xenograft cell lines in mice. This technique enables precise tumor placement for evaluating therapies that must cross the blood-brain barrier.

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5 minutes

We would like to thank all past and present patients and staff at Mayo Clinic for making this work possible.

This protocol was approved by and follows the animal care guidelines of Mayo Clinic. We use athymic nude mice from Charles River. Ensure your tools for injection are prepared according to your institutional IACUC guidelines. The GBM PDX line has been developed by us, and the details about this cell line can be found in Vaubel et al.1.
1. At least 24 h Prior to injections
<ol>
	<li>Ensure sufficient mouse numbers are in-house for the planned experiment. Select only healthy animals for injections. Have an extra cage of mice available for every injection, should issues be encountered (e.g., failure to be anesthetized, etc.).&#160;Provide moist chow or a nutritionally fortified gel diet to all mice 2-5 days prior to injection.</li>
	<li>Sterilize an adequate number of instruments based on the number of animals used for injections. These instruments include thumb forceps, wound clip applicator, 9mm wound clips, and wound clip removal forceps. Other instruments/tools that may be needed include a large pair of operating scissors and a needle holder.</li>
</ol>
2. Cell line preparation
<ol>
	<li>Ensure that the prepared cells are at the appropriate density (100-300,000 per mouse for GBM PDX in 3 &#181;L of phosphate-buffered saline (PBS)). For cell counting, use trypan blue and select viable cells (trypan blue-negative). If the cell preparation contains a substantial amount of debris (trypan-blue positive) cells, the risk of surgical complications increases. Cell preparations with &#62;50% trypan-blue positive cells should not be attempted.</li>
	<li>Cells are viable on ice for up to 4 h. Make a note of the time the cells were first placed on ice for the surgical team. If injections take longer than 4 h, a fresh batch of cells should be prepared. All prepared cells should include at least 25%-30% overage to account for loss.</li>
	<li>Use a 1.5 mL microcentrifuge tube, or similar receptacle to accommodate needle loading.</li>
</ol>
3. Surgery
<ol>
	<li>Prepare the procedure room at the same time as cells are being prepared. Spray down all surfaces with disinfectant, allowing the product to sit for the appropriate contact time. Perform intracranial injections in groups of 5 (up to 60 total animals). Divide the process into four distinct stations (preparation, surgery, injection, and recovery).</li>
	<li>Adhere to strict sterile technique to provide the best possible surgical outcomes. Set all heating support pads to low, if adjustable, and cover them with a disposable protective barrier to prevent direct contact with the mice.</li>
	<li>Stock the prep station with a scale, anesthetic, a heat source covered by a disposable pad, artificial tears, ethanol, povidone-iodine, diluted carprofen-filled syringes, and Radio Frequency Identification (RFID) chips if using.</li>
	<li>On the surgical station, place a large sterile drape on top of a heating pad to create a sterile field. Using sterile technique, drop sterilized instruments, sterilized drill bits, sterile drapes, bone wax, sterile gauze pads, sterile scalpels, and sterile drill wrap onto the sterile field. Other supplies may include drill components and sterile cotton tipped applicators. This station should also have access to a pair of sterile sleeves and an adequate number of sterile gloves. If able and using an adjustable drill, set the speed to ~15,000-20,000 RPM.</li>
	<li>The injection station should be equipped with injection jigs outfitted with autoinjector pumps. Verify that the pumps are correctly set up and the injection jig arms are vertical, square, and locked in place. The autoinjector control unit should be programmed to use a 10 &#181;L glass syringe with a 26G needle (Syringe ID = 0.460 mm) at an infusion rate of 1 &#181;L/ min and a total volume of 3.0 &#181;L. Using sterile technique, open and insert 10 uL Hamilton syringes into the syringe holder of each jig.</li>
	<li>The recovery station should be out of the way and equipped with a heating pad.</li>
	<li>Obtain the cells and begin the procedure as described below.</li>
	<li>Anesthetize mice using an approved method. Weigh individual mice and administer a mixture of 100 mg/kg Ketamine and 10 mg/kg Xylazine diluted with sterile PBS, with a dosing volume of 10 mL/kg, intraperitoneally (IP). Mouse strain may affect the duration of the anesthesia effect; this dose will provide adequate anesthesia to athymic nude mice for ~60 min. 
	NOTE: Once mice are anesthetized, it is best practice to provide supplemental oxygen. In this format, it would be easiest to do this with an oxygen line at Station 1. Place the O2 line into the cage, then top with lid, for 5 minutes before injecting the mice with anesthesia and continue to provide oxygen to anesthetized mice until just before transferring to Station 2. Alternatively, or in addition, provide oxygen supplementation when mice are returned to their home cage, by the same process of placing an O2 line into their cage with a lid to contain the gas. If possible, monitor each animal&#39;s oxygen saturation throughout the procedure with an SpO2 monitor. Provide supplemental oxygen to the animal if the SpO2 drops below 95% while on room air.</li>
	<li>Prior to proceeding, confirm mice are in an adequate plane of anesthesia. Mice should be non-ambulatory and non-reactive to toe pinching or other stimuli. Apply artificial tears to the eyes and prepare the surgical site (mid-snout to shoulders). Using a sterile cotton-tipped applicator, scrub the incision site with 70% ethanol, starting at the top of the head and moving outward in a spiral pattern. Repeat using povidone-iodine. Perform a total of three alternating applications of ethanol and povidone-iodine.</li>
	<li>If using RFID chips for identification, also prepare the skin, from midline to right flank, as described above, and insert the chip subcutaneously.</li>
	<li>Administer analgesics according to your institutional IACUC guidelines. Carprofen (50 mg/mL) diluted with sterile saline to administer 20 mg/kg, subcutaneously (SQ), every 24 h. Note the time of administration. Place the anesthetized mice on a clean paper towel and hand them off to the surgical station.</li>
	<li>While one experimenter is preparing mice, the experimenter at the surgical station should don sterile sleeves and gloves. Position the sterile supplies in an organized manner, allowing for the center of the field to remain open for mice. With assistance, place the sterile drill wrap over the drill.</li>
	<li>Grab the prepared skin of the anesthetized mice at the nape using forceps and transfer from the paper towel to the cotton gauze in the sterile field.</li>
	<li>Apply pressure to the skin of the skull and make a ~1 cm midline incision from the back of the skull to just behind the back of the eyes using a scalpel; repeat for all mice.</li>
	<li>Locate the bregma and move the bit to the injection site (below, Figure 1) using the width of the bit to approximate at 1.0 mm forward and 2.0 mm lateral (right).</li>
	<li>When ready, turn on the drill and apply slight pressure with the drill bit to the skull. Immediately remove pressure once the drill bit penetrates the skull. Repeat the drilling process for all mice. Transfer mice back to the paper towel to hand off to the injection station.</li>
	<li>While one experimenter is drilling the burr hole, another experimenter should use the auto injection pumps to load cells into needles as described below.
	<ol>
		<li>Remove cells from the ice bucket and flick the tube to mix. Make sure cells are a homogeneous suspension.</li>
		<li>Use the pump to load between 3.1-3.5 &#181;L of cells into the syringe. Cell suspension should be cloudy. If clear, likely there is a clog. Flush the needle with sterile PBS or replace.</li>
		<li>Do not touch the tip of the needle to the bottom of the microcentrifuge tube as this will dull the needle. Repeat steps 3.17.1.-3.17.2. until all needles are loaded. Verify that each needle has a volume &#62;3.1 &#181;L.</li>
		<li>After loading cells, recap cells and return to wet ice. Clean the tip of the needle with a sterile alcohol wipe to remove excess cells and avoid seeding in the meninges.</li>
	</ol>
	</li>
	<li>Load the mice onto the bite blocks and place ear pins (Figure 2). Ensure that the skull is secure and level in both planes. Adjust as necessary. To preserve as much body heat as possible, animals should be covered from the shoulders to the haunches with plastic wrap during injections.</li>
	<li>Use a sterile cotton swab to move the skin out of the way so both the Bregma and burr hole are visible.</li>
	<li>Place the tip of the needle over the bregma, just above the skull, and dial in the coordinates below: 1.0 mm forward and 2.0 mm lateral (right).</li>
	<li>Lower the needle tip so the bevel is at the top of the skull. Dial in a depth of 3 mm from the top of the skull and start the pump(s). When the pump stops injecting cells, wait at least 1 min before removing the needle from the brain. Remove mice from bite blocks and place on a paper towel to transfer back to the surgical station. For infusions &#62;3 &#181;L, wait at least 5 min before removing the needle from the injection site.</li>
	<li>At the surgical station, break off a pea-sized amount of bone wax and roll in fingers to soften. &#160;Use sterile forceps to transfer mice back to the surgical field as before. Use non- dominant hand to separate the skin to expose the burr hole and gently swipe the wax over the burr hole once to seal. Avoid excessive force/swipes/bone wax application as this can cause intracranial pressure issues.</li>
	<li>Use 1-2 wound clips or 4-0 Vicryl suture with 1-2 simple interrupted suturing to close the head incision. Ensure closures are secure but not overly tight. Mice should be able to easily close their eyes, and there should be no pulling of eyelids or skin. Transfer the mice back to the paper towel for recovery.</li>
</ol>
4. Post-surgery care
<ol>
	<li>If using a strain that is sensitive to injectable anesthesia (e.g., NSG), provide a reversal agent. Atipamezole (5 mg/mL) diluted to 0.1 mg/mL with sterile saline, administered IP at 0.25 mg/kg to 1.0 mg/kg, assuming a 10 mL/kg dosing rule.</li>
	<li>Return mice to home cage on heat source. Cage should be 1/3 off heat.</li>
	<li>Actively monitor mice until they have regained consciousness (~1 h). Every 20 min, perform manual handling (picking up, rubbing, stimulating) and gentle toe pinching until all mice in the cage are ambulatory. Return recovered mice to the animal housing room.</li>
	<li>Monitor the mice daily for at least 10-14 days following surgery. Provide moist chow or a nutritionally fortified gel diet for at least the first 3 days post-op. Monitor the hydration status of all mice and provide SQ fluids if necessary.</li>
	<li>Continue SQ Carprofen every 24 h, for at least 2 days post-op, then as needed based on individual mouse recovery.</li>
	<li>Any postoperative weightloss should begin to recover in 2-3 days. Incision sites should be closed within 3-4 days. Check institutional IACUC guidelines for how long surgical closures are required. Mayo Clinic policy mandates 10 days.</li>
	<li>Following surgical recovery, continue monitoring mice daily for signs of neurological decline. Symptoms will include circling, paralysis, seizures, and lethargy.</li>
	<li>Once moribund criteria are met, animals must be euthanized as per institutional guidelines. Harvest brains and fix in formalin to allow for tumor confirmation. These tumors will be readily visible by H&#38;E and/or immunofluorescence (Figure 3).</li>
</ol>

<ol><li>Vaubel, R. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Genomic+and+Phenotypic+Characterization+of+a+Broad+Panel+of+Patient-Derived+Xenografts+Reflects+the+Diversity+of+Glioblastoma%5BTitle%5D)+AND+%22Clin+Cancer+Res%22%5BJournal%5D)">Genomic and Phenotypic Characterization of a Broad Panel of Patient-Derived Xenografts Reflects the Diversity of Glioblastoma.</a> Clin Cancer Res. 26 (5), 1094-1104 (2020).</li>
<li>Porath, K. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Convection+enhanced+delivery+of+EGFR+targeting+antibody-drug+conjugates+Serclutamab+talirine+and+Depatux-M+in+glioblastoma+patient-derived+xenografts%5BTitle%5D)+AND+%22Neurooncol+Adv%22%5BJournal%5D)">Convection enhanced delivery of EGFR targeting antibody-drug conjugates Serclutamab talirine and Depatux-M in glioblastoma patient-derived xenografts.</a> Neurooncol Adv. 4 (1), vdac130(2022).</li>
<li>Marin, B. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Heterogeneous+delivery+across+the+blood-brain+barrier+limits+the+efficacy+of+an+EGFR-targeting+antibody+drug+conjugate+in+glioblastoma%5BTitle%5D)+AND+%22Neuro+Oncol%22%5BJournal%5D)">Heterogeneous delivery across the blood-brain barrier limits the efficacy of an EGFR-targeting antibody drug conjugate in glioblastoma.</a> Neuro Oncol. 23 (12), 2042-2053 (2021).</li>
<li>Jain, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Bystander+Effects%2C+Pharmacokinetics%2C+and+Linker-Payload+Stability+of+EGFR-Targeting+Antibody-Drug+Conjugates+Losatuxizumab+Vedotin+and+Depatux-M+in+Glioblastoma+Models%5BTitle%5D)+AND+%22Clin+Cancer+Res%22%5BJournal%5D)">Bystander Effects, Pharmacokinetics, and Linker-Payload Stability of EGFR-Targeting Antibody-Drug Conjugates Losatuxizumab Vedotin and Depatux-M in Glioblastoma Models.</a> Clin Cancer Res. 30 (15), 3287-3297 (2024).</li>
<li>Baumann, B. C., Dorsey, J. F., Benci, J. L., Joh, D. Y., Kao, G. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Stereotactic+intracranial+implantation+and+in+vivo+bioluminescent+imaging+of+tumor+xenografts+in+a+mouse+model+system+of+glioblastoma+multiforme%5BTitle%5D)+AND+%22J+Vis+Exp%22%5BJournal%5D)">Stereotactic intracranial implantation and in vivo bioluminescent imaging of tumor xenografts in a mouse model system of glioblastoma multiforme.</a> J Vis Exp. (67), e4089(2012).</li>
<li>Ozawa, T., James, C. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Establishing+intracranial+brain+tumor+xenografts+with+subsequent+analysis+of+tumor+growth+and+response+to+therapy+using+bioluminescence+imaging%5BTitle%5D)+AND+%22J+Vis+Exp%22%5BJournal%5D)">Establishing intracranial brain tumor xenografts with subsequent analysis of tumor growth and response to therapy using bioluminescence imaging.</a> J Vis Exp. (41), e1986(2010).</li>
<li>Bausart, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Mismatch+between+Bioluminescence+Imaging+%28BLI%29+and+MRI+When+Evaluating+Glioblastoma+Growth%3A+Lessons+from+a+Study+Where+BLI+Suggested+%26%2334%3BRegression%26%2334%3B+while+MRI+Showed+%26%2334%3BProgression%26%2334%3B%5BTitle%5D)+AND+%22Cancers+%28Basel%29%22%5BJournal%5D)">Mismatch between Bioluminescence Imaging (BLI) and MRI When Evaluating Glioblastoma Growth: Lessons from a Study Where BLI Suggested &#34;Regression&#34; while MRI Showed &#34;Progression&#34;.</a> Cancers (Basel). 15 (6), cancers15061919(2023).</li>
<li>Su, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((An+optimized+bioluminescent+substrate+for+non-invasive+imaging+in+the+brain%5BTitle%5D)+AND+%22Nat+Chem+Biol%22%5BJournal%5D)">An optimized bioluminescent substrate for non-invasive imaging in the brain.</a> Nat Chem Biol. 19 (6), 731-739 (2023).</li>
<li>Paxinos, G., Franklin, K. B. J. <a target="_blank" href="http://scholar.google.com/scholar?hl=en&safe=off&q=author%3aPaxinos%2C+G+%22The+mouse+brain+in+stereotaxic+coordinates%3A+hard+cover+edition%22">The mouse brain in stereotaxic coordinates: hard cover edition</a>. , Elsevier. https://labs.gaidi.ca/mouse-brain-atlas (2001).</li>
<li>Sarkaria, J. N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Is+the+blood-brain+barrier+really+disrupted+in+all+glioblastomas%3F+A+critical+assessment+of+existing+clinical+data%5BTitle%5D)+AND+%22Neuro+Oncol%22%5BJournal%5D)">Is the blood-brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data.</a> Neuro Oncol. 20 (2), 184-191 (2018).</li>
</ol>

An experimental toolkit that includes orthotopic models will enable researchers to study CNS tumors in their relevant microenvironment. Particular emphasis should be placed on cell preparation, animal selection, and cell injection. Cells that are cultured with diligent care will serve as more reliable experimental tools than those kept in suboptimal conditions. Animal condition is also an important determinant in overall surgical success, so intentional focus on health and welfare should be applied. Lastly, correct cell ...

GBM remains a lethal disease despite decades of intensive research. More relevant models must be implemented if preclinical modeling is to be more predictive of clinical responses. As such, we sought to develop a GBM PDX collection using freshly resected patient specimens from Mayo Clinic. This collection was characterized and found to be highly representative of clinical GBM1. The overall goal of this protocol is to share a technically rigorous, highly reproducible intracranial implantation technique that we have refined over the past 20 years. The current iteration of this method emphasizes many surgical principles, such as sterile technique and postoperative care, and should be suitable for most applications that aim to study intracranial tumors. While the protocol in its current form is written for intracranial cell implantations within the cerebrum, injection coordinates and volumes can be modified to accommodate seeding within different anatomical structures within the brain. Moreover, this protocol can also be adapted for intracranial therapeutic infusions as well2,3,4.
A vast majority of intracranial implantation protocols rely on bioluminescence imaging to confirm tumor growth after surgery5,6. Several reports have observed significant discordance between luminescence counts and overall tumor burden, thereby limiting the reliability of such data for confirmatory assays7,8. In lieu of this indirect approach, we confirm success using a combination of survival endpoints and histological confirmation by Hematoxylin and Eosin (H&#38;E) staining, especially in situations where other variables may be at play (e.g., procedures, dosing, etc.). Viral transduction approaches may also alter the state of the BBB, which would have negative consequences for future therapeutic efficacy evaluations.

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stereotactic intracranial implantation of glioblastoma patient-derived xenograft cell lines in mice

Stereotactic Intracranial Implantation of Glioblastoma Patient-derived Xenograft Cell Lines in Mice

The development of efficacious treatment regimens has been challenging for central nervous system tumors, in part due to the limited availability of translationally relevant preclinical models. Glioblastoma (GBM) is the most common and aggressive primary brain tumor and is the focus of this research. Established cell line-derived models do not accurately reflect the genetic heterogeneity of human diseases. This is of particular concern in the current landscape, where a majority of pharmaceuticals are targeting tumor-specific alterations. Moreover, studies that leverage subcutaneous xenografts are technically easier to execute, but the blood-brain barrier (BBB) is completely absent. As one of the features responsible for treatment failure in neuro-oncology, the BBB must be considered when evaluating any novel therapeutic strategy. Therefore, intracranial placement is of critical importance. We have established and characterized over 100 GBM patient-derived xenograft (PDX) intracranial models to support therapeutic evaluation efforts. Here, we describe the stereotactic implantation technique that we utilize for these studies.

This implantation technique should produce minimal post-operative complications with very rare post-operative death (&lt;5%) and high levels of tumor take (90+%). Body weight monitoring and overall activity levels during the post-operative period represent two surrogate markers for recovery. Peak body weight loss should occur within 24 h of surgery and fully resolve within 72-96 h if no post-operative complications arise (Figure 4).
Immediate observations that sug...

The goal of this protocol is to provide researchers with a highly reproducible technique for intracranial implantations.

The development of efficacious treatment regimens has been challenging for central nervous system tumors, in part due to the limited availability of ...

stereotactic-intracranial-implantation-glioblastoma-patient-derived

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Stereotactic Adoptive Transfer of Cytotoxic Immune Cells in Murine Models of Orthotopic Human Glioblastoma Multiforme Xenografts

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Translational Orthotopic Models of Glioblastoma Multiforme

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Nanoparticle Delivery of an Oligonucleotide Payload in a Glioblastoma Multiforme Animal Model

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Establishment of Orthotopic Patient-derived Xenograft Models for Brain Tumors using a Stereotaxic Device

Learn stereotactic intracranial implantation of glioblastoma patient-derived xenograft cell lines in mice. This technique enables precise tumor placement for evaluating therapies that must cross the blood-brain barrier.

Stereotactic Intracranial Implantation of Glioblastoma Patient-derived Xenograft Cell Lines in Mice

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