In The May Issue
- 5 Most Interesting Aptamer Selections
- Meet with Base Pair in Boston
- Aptamer Targeting of Brain Tumors: Crossing the Blood-Brain Barrier
5 Most Interesting Aptamer Selections
Aptamers can be selected to bind almost any kind
of molecule in almost any kind of environment, making them attractive candidates for a wide range of applications.
Click Here to read about some of the most interesting aptamer selections Base Pair has performed.
Meet with Base Pair in Boston
Coming to Boston for the Biomarkers and Immuno-Oncology World Congress June 11-13? Set up a meeting with a Base Pair aptamer specialist to learn more about aptamers in biomarker discovery, biomarker/drug detection and monitoring, and targeted drug delivery.
Aptamer Targeting of Brain Tumors: Crossing the Blood-Brain Barrier
Therapeutic design for the treatment of brain
diseases presents specific challenges. The drug must evade the body’s circulatory defenses long enough to reach the brain. It must then cross the blood-brain barrier. Lastly, it must deliver treatment to infected cells with minimal damage to normal cells and tissues. Researchers at the Zhongshan Hospital of Xiamen University and the Chinese People’s Liberation Army General Hospital of Beijing Military Region in China recently developed a new construct for targeted drug delivery to the brain. Orthotopic implantation of glioma, a malignant brain tumor, was used to evaluate the effectiveness of several nanoparticle constructs for targeted drug delivery in BALB/c mice.
Enhancing In Vivo Stability
The reticuloendothelial system (RES) is a network of cells and tissues involved with the phagocytosis and clearance of foreign particles and microbes (2). Evading this natural defense system is one challenge in the design of therapeutic nanoparticles. The function of the RES involves opsonization, or adsorption of proteins onto the surface of foreign particles. Attaching hydrophilic polyethylene glycan (PEG) is one method of interfering with opsonization and extending the half-life of nanoparticles in vivo (4).
In the present study, addition of PEG to biocompatible gelatin-siloxane nanoparticles (GS NPs) extended their time in circulation and decreased detection of GS NPs in the kidney. There was strong signal in the kidney over a period of one to four hours without PEG. No signal in the kidney and weak signal in the circulation was visible for up to four hours with PEG-modified GS NPs, demonstrating improved stability and therapeutic availability (3).
Crossing the Blood-Brain Barrier
The blood-brain barrier (BBB) is a membrane interface that surrounds the brain. The barrier is designed to prevent infiltration of toxins and pathogens, while selectively enabling the uptake of nutrients. Most therapeutic compounds cannot cross the BBB, creating a strong need for selective delivery of therapeutics to the brain for treatment of neurological disorders, brain tumors, and ischemic cerebral disorders (3).
Based on the success of specialized peptides to promote entry into cells and to facilitate transport of drug-conjugated nanoparticles across the BBB, the research team added a cationic tat cell-penetrating peptide to promote adsorption-mediated transcytosis and delivery of conjugated nanoparticles into the brain. In the mouse glioma model, tat-conjugated functionalized nanoparticles generated stronger signal in the brain than functionalized nanoparticles without the tat peptide (3).
Targeting Glioma
While evasion of the host defense system and penetration of the blood-brain barrier are huge obstacles, another concern is potential damage to normal cells and tissues. Off-target effects can limit potential therapeutic doses and overall therapeutic effectiveness. One approach to targeted drug delivery utilizes selective aptamers. Aptamers are short strands of DNA or RNA with unique secondary and tertiary structures that are selected to bind to a specific target of interest. Aptamers are small, typically non-immunogenic, and easily conjugated without loss of binding affinity, making them ideal for use in nanoparticle drug delivery and cell targeting. Aptamers can be selected to bind a wide range of targets, including small molecules, protein receptors, amino acids, and specific cells. (1,3).
The research team in China used a tumor-targeting aptamer, TTA1, to enhance delivery of the NP construct to the glioma. TTA1 binds selectively to tenascin-c (TN-C), an extracellular matrix protein overexpressed on the surface of gliomas and other tumor cells. Upon dissection, signal from aptamer-functionalized GS NPs was localized in the area of the brain with the glioma (see image “p” at the beginning of this article), showing the effectiveness of the aptamer in promoting targeted drug delivery (3).
A 3-Pronged Approach
In the end, gelatin-siloxane nanoparticles conjugated to PEG, TTA1 aptamer, and the tat-peptide (Tat–TTA1–PEG–GS NPs) generated the strongest and most localized fluorescent signal, indicating effective delivery to glioma in the mouse brain (3). Cell-targeting aptamers are a critical component in promising new constructs for drug delivery.
Custom Aptamer Selection for Cell Targeting
A growing number of researchers are looking to utilize aptamers for targeted drug delivery. The ability to select aptamers to a purified cell surface protein or select aptamers using actual cells both simplifies and speeds the process of developing selective affinity reagents.
Contact Base Pair today for more information on selection of aptamers to specific cell types.
References:
1. Jayasena, S. D. Aptamers: An emerging class of molecules that rival antibodies in diagnostics. Clinical Chemistry. 1999. 45(9):1628-1650.
2. Lazer, G., et al. The Role of the Reticuloendothelial System in Natural Immunity. Natural Immunity. 2005. pp. 95-101.
3. Lin, X., et al. Highly efficient glioma targeting of Tat peptide-TTA1 aptamer-polyethylene glycol-modified gelatin-siloxane nanoparticles. Journal of Neuroscience and Nanotechnology.
4. Petros, R.A. and Joseph M. DeSimone. Strategies in the design of nanoparticles for therapeutic applications. Nature Reviews: Drug Discovery. 2010. 9: 615-627.
5. Pulicherla, K. K. and Mahendra Kumar Verma. Targeting therapeutics across the blood brain barrier (BBB), prerequisite towards thrombolytic therapy for cerebrovascular disorders—an overview and advancements. AAPS PharmSciTech. 2015. 16(2):223-333.