Dendrimer-Functionalized Nanodiamonds as Safe and Efficient Drug Carriers for Cancer Therapy: Nucleus Penetrating Nanoparticles

Abstract

Nanodiamonds (NDs) are increasingly being assessed as potential candidates for drug delivery in cancer cells and they hold great promise in overcoming the side effects of traditional chemotherapeutics. In the current work, carboxylic acid functionalized nanodiamonds (ND-COOH) were covalently modified with poly­(amidoamine) dendrimer (PAMAM) to form amine-terminated nanodiamonds (NP). Unlike ND-COOH, the chemically modified nanodiamond platform NP revealed a pH-independent aqueous dispersion stability, enhancing its potential as an effective carrier. Physical encapsulation of poorly water soluble cabazitaxel (CTX) drug on NP formed ND-PAMAM-CTX (NPC) nanoconjugates and substantially reduced the size of CTX from micrometer to nanometer. CTX was localized within the pores of nanoparticle aggregates and the cavities of the PAMAM dendrimer, thus facilitating the loaded drug’s controlled and sustained release. NPC’s cumulative CTX release efficiency was determined to be ∼95% at pH 4 after 96 h. A high cellular uptake of NPC both within the cytoplasm and nucleus of U87 cells is confirmed, accounting for a reduced IC50 value (1 nM). Both the cell cycle and Western blot analyses confirmed enhanced cell death and suppressed tubulin protein expression in NPC-treated cells. A significantly high inhibition to cell division with early apoptosis and reduced metastasis demonstrates the effective loading of CTX dosages on the nanocarrier. The present work highlights the potential of a newly designed nanocarrier NP as an efficient nanocargo for cellular delivery applications and may provide future insights to treat one of the most aggressive tumors in neuro-oncological research, glioblastoma multiforme (GBM).

Fluorescent Nanocarbons: From Synthesis and Structure to Cancer Imaging and Therapy

“…[477] Many investigators have tested the conjugation of NDs to several types of drug molecules, including epirubicin, [478] DOX, [479][480][481][482] tamoxifen, [483] cetuximab, [484] and amonafide, [485] and assessed their delivery capabilities, uptake, and internalization after reaching a tumor region. Patil et al [486] demonstrated that NDs could be covalently conjugated to poly(amidoamine) dendrimer (PA-MAM) via an ultrasound probe sonication to form ND-PAMAM nanoconjugates. The capabilities of cabazitaxel (CTX) as a guest molecule to be localized within the accessible nanoconfined spaces of ND-PAMAM conjugates and internal cavities of the PA-MAM dendrimers were investigated.…”

“…Patil et al. [ 486 ] demonstrated that NDs could be covalently conjugated to poly(amidoamine) dendrimer (PAMAM) via an ultrasound probe sonication to form ND‐PAMAM nanoconjugates. The capabilities of cabazitaxel (CTX) as a guest molecule to be localized within the accessible nanoconfined spaces of ND‐PAMAM conjugates and internal cavities of the PAMAM dendrimers were investigated.…”

Protein Delivery to the Cytosol and Cell Nucleus via Micellar Nanocarrier-Based Nonendocytic Uptake

“…4,5 Thus, the carrier needs to be appropriately designed in terms of size/surface chemistry for endosomal escape and for efficient nucleus delivery. 1−3 Some of the examples of nucleus delivery include a tiopronincoated Au nanoparticle of 2 nm size for gene delivery to the nucleus, 6 peptide-conjugated chitosan nanoparticle (25 nm, 100 nm) for protein delivery to the nucleus, 7 3−4 nm carbon dot for nuclear delivery of the molecular drug, 8 dendrimerfunctionalized nanodiamond of 200−400 nm size for nuclear delivery of the molecular drug, 9 cell-penetrating protein-based protein delivery to the nucleus via endosomal escape, 10 and polythymidine-based oligonucleotide delivery to the nucleus via mechanotransduction. 11,12 Recent studies show that nonendocytic and direct cell membrane penetration-based cell delivery can be a powerful alternative for subcellular delivery, as these processes can bypass the endosomal/lysosomal entrapment.…”

“…Delivery of small-molecule drugs, genes, macromolecules, and proteins into the cell and subcellular compartment is important for efficient therapeutic performance. , In particular, efficient cell nucleus delivery of exogenous materials can greatly improve the biochemical activity. In a common approach, synthetic carriers are used for nucleus delivery where drug-loaded/conjugated carriers enter into the cell via cellular endocytosis. − However, such a delivery approach restricts the nuclear delivery of exogenous materials as they enter the cytosol with a vesicular coating (not freely available in the cytosol) and trapped in the endosome/lysosome (and often enzymatically degraded). , Thus, the carrier needs to be appropriately designed in terms of size/surface chemistry for endosomal escape and for efficient nucleus delivery. − Some of the examples of nucleus delivery include a tiopronin-coated Au nanoparticle of 2 nm size for gene delivery to the nucleus, peptide-conjugated chitosan nanoparticle (25 nm, 100 nm) for protein delivery to the nucleus, 3–4 nm carbon dot for nuclear delivery of the molecular drug, dendrimer-functionalized nanodiamond of 200–400 nm size for nuclear delivery of the molecular drug, cell-penetrating protein-based protein delivery to the nucleus via endosomal escape, and polythymidine-based oligonucleotide delivery to the nucleus via mechanotransduction. , …”

Stimuli-Responsive Dendritic Macromolecules for Optical Detection of Metal Ions and Acidic Vapors by the Photoinduced Electron Transfer Mechanism: Paper-Based Indicator for Food Spoilage Sensing

“…Dendritic macromolecules have lots of unique properties, which are well-defined nanostructures and unique morphologies, high concentration of functional groups at the surface, high solubility in aqueous media, high monodispersity, low viscosity, and modification ability with functional molecules. − These characteristics resulted in the development of dendritic nanostructures for a wide range of applications, including drug-delivery or gen-delivery systems, chemosensors, bioimaging, and tissue engineering. − Induction of stimuli-responsivity to dendrimers by their modification with intelligent molecules has been known as an attractive field of study. The pH- or temperature-responsive dendrimers are among the highly important smart nanocarriers in drug- or gen-delivery technology, − and the light-responsive dendrimers are highly applicable in bioimaging and photosensing applications. , Different types of dendrimers were modified with stimuli-responsive molecules using their surface functional groups, or in a classic approach, using a functional intelligent molecule as a core to growth of dendritic structures on the surface. − Therefore, the presence of acid, amine, or hydroxyl functional groups on dendrimers is inevitable for their reaction with functional molecules.…”