Scientists have recently developed amine-terminated nanodiamonds (ND) by modifying carboxylic acid-functionalized nanodiamonds (ND-COOH) with poly (amidoamine) dendrimers (PAMAM). The new ND design presented high potential as a candidate for drug delivery to cancer cells. This study is available as an accepted manuscript in ACS Applied Bio Materials.
Study: Nanodiamonds functionalized with dendrimers as carriers of safe and efficient drugs for cancer therapy: penetrating nanoparticles of the nucleus. Image credit: Christoph Burgstedt / Shutterstock.com
Nanodiamonds: A potential candidate for cancer treatment
Although scientists have developed many filler materials to deliver active ingredients through specific cells, there is a search for more stable and secure nanocarriers to improve drug delivery systems. Recently, NDs have been applied in various areas of biomedical research, such as drug and gene delivery and bioimaging. This is because NDs have a high surface-to-volume ratio, are non-cytotoxic, have easy-to-modify surfaces, have high biocompatibility, and are prone to accumulating in tumor cells.
Previous studies have reported that biomolecules can be loaded into NDs by both the physical adsorption method and the covalent graft. NDs are used as a nanocharge due to their large surface area along with the presence of nanometric pores, which help their high payload through physical adsorption.
The use of unmodified NDs as a nanocharge poses many challenges, including aqueous colloidal instability, as they are likely to form aggregates with large agglutination sizes. This drawback could be alleviated by modifying the surface of NDs with macromolecules and polymers.
PAMAM forms a stable interaction between nanoparticle surfaces and a variety of bioactive compounds or payloads. Due to the presence of amine groups (positively charged), a variety of payloads can move across cell membranes rapidly. In addition, it also improves ND aqueous colloidal stability.
Previous studies have reported that fourth-generation PAMAM can evade the ependyma and penetrate the dural surface of the central nervous system (CNS) due to its unique nanotopographic symmetric geometry. However, PAMAM dendrimers are not applied for in vivo applications due to their cytotoxicity.
Cabazitaxel for the treatment of brain tumor
The Food and Drug Administration (FDA) has approved the application of second-generation taxane, cabazitaxel (CTX), for the treatment of metastatic castration-resistant prostate cancer (mCRPC).
Studies have shown that CTX is a promising candidate for the treatment of brain tumors. However, the delivery of the appropriate CTX concentration to the brain is restricted because hydrophobic nanoparticles face obstruction as they cross the blood-brain barrier (BBB).
To overcome this problem of water solubility, commercially available CTX contains a large amount of co-solvent (e.g., polysorbate 80 and ethanol); however, these excipients cause neurotoxicity and hypersensitivity.
Efficacy of ND-PAMAM-CTX for the treatment of cancer
In a new study, researchers have strategically designed and synthesized a nanocharge, i.e., PAMAM-modified ND-loaded CTX (ND-PAMAM-CTX) in nanocrystalline form. ND-PAMAM-CTX has shown considerable improvement in cell intake and has increased the efficacy of the drug at low doses.
In this study, the researchers used the ultrasonic probe homogenization method to charge microcrystalline CTX to NP to form an ND-PAMAM-CTX (NPC) nanoconjugate. The scientists reported that NP allows the encapsulation of water-soluble CTX weekly in nanocrystalline form, with improved load capacity.
The researchers observed that there was a considerable decrease in the size of the ND particles with increasing pH. This is due to the ionization of the carboxylic group on the surface, which inhibited aggregation due to electrostatic repulsions. The TEM image of crystalline ND-PAMAM-CTX revealed a rod-shaped morphology, the size of which ranged from 130 to 200 nm.
The researchers used a UV-vis spectrophotometer to determine the amount of CTX charge in an NP carrier. They reported that the loading capacity was 8.2 μg / mL, 11.0 μg / mL and 6.4 μg / mL at pH 4, 6 and 7.4, respectively. The scientists reported that the accumulated release of CTX from the NPC nanoconjugate depended on pH.
At acidic pH, the accumulated CTX release from NPC was high due to protonation of the cavity of the PAMAM dendrimer. This event influenced the conformational changes and the weakening of the links between the dendrimer and the drug. This is one of the most important features of the nanocarrier for cancer treatment because the release of the drug in the acidic state is analogous to the pH level of a cancerous microenvironment.
The scientists also evaluated the effect of NPC and crystalline CTX on glioblastoma multiforme (GBM), one of the most aggressive forms of cancer that begins in the brain. They observed that nanoparticles loaded with newly designed CTX drugs rapidly penetrated the cells, located mainly in the cytoplasm and colocalized in the nucleus.
The authors reported that the new nanocargo not only was able to cross deeper brain parenchyma sites, but significantly inhibited cell migration at a low concentration of CTX to the NPC nanoconjugate. In addition, ND-PAMAM-CTX also increased the antimetastastic effect at low doses.
The current study provides a mechanistic view of how ND-PAMAM-CTX interacts with cancer cells. The researchers stated that ND-PAMAM-CTX was responsible for supporting the suppression of tubulin depolymerization and the reduction of tubulin proteins, which are important for cell division. The authors believe that the use of ND-PAMAM-CTX could be an effective and safe treatment for brain tumors in the future.
Reference
Patil, S. et al. (2022) Nanodiamonds functionalized with dendrimers as carriers of safe and efficient drugs for cancer therapy: core-penetrating nanoparticles. Applied biomaterials ACS. https://pubs.acs.org/doi/10.1021/acsabm.2c00373.
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