Dendrimer-based Drug Delivery Systems Research Articles

Potential of Dendrimers in Drug Delivery: An Updated Review

Dendrimers have become a choice, for delivering drugs at the nano level thanks to their structure that allows precise control over size, shape, and surface features. This summary gives an update on progress in using dendrimers for drug delivery. To start with it talks about the ways dendrimers are customized for drug delivery needs like modifying their surfaces to make them more compatible with the body and targeting specific delivery sites. By adding elements that respond to conditions like pH or temperature they can release drugs in a controlled manner when needed. The summary also looks at developments using dendrimer-based formulations for types of therapeutic substances such as small molecules, peptides, proteins, and genetic material. These formulations have shown performance in how drugs move through the body, effectiveness in treating illnesses, and fewer side effects compared to methods of drug delivery. It also covers studies done before applying these systems in real-life blood-brain situations and how they could help get past barriers within the body like the blood-brain barrier or deliver drugs directly to tissues or cells - improving treatments while reducing overall harm. Lastly, it touches on obstacles and future paths, for research involving dendrimers like making them more scalable and consistent well as meeting regulatory standards. It is essential to overcome these obstacles to successfully transition dendrimer-based drug delivery systems, from research labs to use thereby harnessing their capabilities to transform drug delivery and personalized medicine.

Recent advances in dendrimer-based drug and gene delivery system

Recent advances in dendrimer-based drug and gene delivery system

Dendrimer and dendrimer gel-derived drug delivery systems: Breaking bottlenecks of topical administration of glaucoma medications.

Due to high structural flexibility, multidrug carrying capability, and tunable size, dendrimers have been used as suitable carriers for ophthalmic drug delivery. Drug molecules can be either encapsulated or chemically coupled to dendrimers. The nanoscopic size, spheroidal shape, and cationic surface of polyamidoamine (PAMAM) dendrimers promote their interaction with the cornea and result in prolonged precorneal retention. Dendrimers could be further cross-linked to produce three-dimensional hydrogel networks or dendrimer hydrogels (DH). The properties of the DH can be readily adjusted to maintain both fluidity and adhesiveness, making them suitable for developing topical ocular drug formulations. Micro-/nano-sized DHs, that is, dendrimer micro-/nano-gels, have unique properties such as ease of administration, large specific surface area for adhesion, and drug targeting functionalities, making them attractive for ophthalmic drug delivery. This perspective reports advances in PAMAM dendrimer based drug delivery systems including drug conjugates and micro- and nano-gels to enhance and sustain the delivery of multiple anti-glaucoma drugs, Dendrimer and dendrimer gel-derived drug delivery systems hold great potential as multifunctional topical drug delivery systems for the eye.

Dendrimers-Based Drug Delivery System: A Novel Approach in Addressing Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disease that is characterized by the loss of dopamine. Since dopamine has trouble entering the blood–brain barrier, the utilization of dendrimers and other nanomaterials is considered for conjugating the neurotransmitter and other PD drugs. Dendrimers are three-dimensional, hyper-branched structures that are categorized into several generations. Alpha-synuclein (ASN) is the protein involved in regulating dopaminergic functions and is the main aggregate found inside Lewy bodies. Different types of dendrimers have shown efficacy in disrupting the formation of unstable beta structures of ASN and fibrillation. The conjugation of PD drugs into nanomaterials has elicited a prolonged duration of action and sustained release of the drugs inside the BBB. The objectives of this study are to review the applications of a dendrimer-based drug delivery system in addressing the root cause of Parkinson’s disease and to emphasize the delivery of anti-Parkinson’s drugs such as rotigotine, pramipexole and dopamine using routes of administration other than oral and intravenous.

Design, Synthesis, and Bioevaluation of Novel Enzyme-Triggerable Cell Penetrating Peptide-Based Dendrimers for Targeted Delivery of Camptothecin and Cancer Therapy.

Novel enzyme-triggerable cell penetrating peptide (ETCPP) dendrimers with a camptothecin (CPT) warhead were designed and synthesized based on an amphiphilic penetrating peptide (FKKFFRKLL, discovered by us before). Among the newly synthesized ETCPP dendrimer conjugates, BL_Oc-SS-CPT (a high-generation dendrimer) exhibited the highest activity with IC50s in the nanomolar range (31-747 nM) against a panel of cancer cells, which is 3-10 times better than that of CPT. BL_Oc-SS-CPT remained intact during transit to target cells and in normal tissues with a plasma half-life of 4.2 h, 2.3-fold longer than that of the monomer (1.8 h). Once reaching the tumor site, BL_Oc-SS-CPT gradually released CPT in the presence of excessive matrix metalloproteinase-2/9 and GSH in cancer cells. Importantly, BL_Oc-SS-CPT exhibited excellent in vivo tumor targeting capability and antitumor efficacy with benign toxicity profiles. Thus, the novel ETCPP dendrimer-based drug delivery system (e.g., BL_Oc-SS-CPT) represents a safe and effective strategy for targeted cancer therapy.

In-vitro evaluation of dendrimeric formulation of oxaliplatin

The aim of this study is, preparing various dendrimeric formulations of oxaliplatin and investigating their properties. First of all, the solubility enhancement capabilities of polyamidoamine (PAMAM) G3.5 and PAMAM G4.5 dendrimers were investigated. The results showed that oxaliplatin solubility mostly increasing linearly with dendrimer concentration. Additionally, the increase was more notable in PAMAM G4.5 dendrimers. Then, drug–dendrimer complexes were prepared in different mediums, since the medium used can affect the amount of drug-loaded to dendrimers. Prepared complexes were examined for loading capacity and loading efficiency. It was found that PAMAM G4.5 dendrimers can complex with 2- to 5-fold more oxaliplatin than PAMAM G3.5. Finally, oxaliplatin was modified to a platinum (IV) compound to prepare chemical drug–dendrimer conjugates. Ester bonds were established by Steglich esterification through the hydroxyl group of modified oxaliplatin and the carboxyl groups of the dendrimers. The formulations were characterized by UV, IR, NMR spectroscopy, and dynamic light scattering techniques. PAMAM G3.5 conjugate was further evaluated for the cytotoxicity test. The IC50 value of PAMAM G3.5 conjugate was found as 0.72 µM. For unmodified oxaliplatin, this value was 14.03 µM. As a result, a dendrimer-based drug delivery system that has been found promising for further improvement has been developed successfully.

Fe3O4@PEG-coated dendrimer modified graphene oxide nanocomposite as a pH-sensitive drug carrier for targeted delivery of doxorubicin

Since dendrimer-based magnetic nanoparticles have presented remarkable potential as carriers in biomedical applications, it is worthwhile to construct a dendrimer-based drug delivery system for cancer treatment. Hence, in the present study, triazine dendrimer functionalized graphene oxide (GO-DT G2.5) was successfully fabricated by the divergent method. Then, the Fe3O4@PEG nanoparticles were attached to the surface of GO-TD G2.5 (GO-TD-Fe3O4@PEG) as a new magnetic nanocarrier for effective loading and the pH-responsive release of Doxorubicin (DOX). The structure and morphology of the synthesized GO-TD-Fe3O4@PEG were characterized by BET, XRD, DLS/ Zeta potential, UV–vis, FT‐IR, AFM, SEM, and VSM analysis. The surface morphology indicated that the average thickness of the sheets in the synthesized nanocarrier had approximately 144.21 nm. The encapsulation efficiency (EE) and drug-loading content (DLC) of this system were obtained ~92.6 and ~9.26%, respectively. The in vitro release studies of DOX from GO-TD-Fe3O4@PEG were performed at various pH values and found that the release process was noticeably controlled pHresponsive behavior. In vitro cytotoxicity studies of the as-synthesized GO-TD-Fe3O4@PEG against normal cell line (MCF-10A) and breast cancer cell line (MCF-7) confirmed that the non-toxic GO-TD-Fe3O4@PEG has excellent biocompatibility. DAPI staining and apoptosis analysis by flow-cytometry demonstrated that the apoptotic effects of GO-TD-Fe3O4@PEG-DOX have higher in comparison to free DOX. Cellular uptake also showed a high uptake percentage for GO-TD-Fe3O4@PEG-DOX than free DOX within 4 h. Therefore, the obtained results in this work suggesting that GO-TD-Fe3O4@PEG nanocomposite is a promising nanocarrier for targeted delivery and controlled release of anticancer drugs for biomedical applications.

Understanding Physico-chemical Interactions of Dendrimers with Guest Molecules for Efficient Drug and Gene Delivery

Drug and gene deliveries are crucial aspects in biomedical application as they stimulate biological response of the body to elicit a therapeutic effect. It is seen that drugs, their formulations and the route of administrations, play a vital role in enhancing therapeutic effect onto the desired cellular or intracellular target. But, conventional drug forms suffer from poor pharmacodynamics and pharmacokinetics profile. For this purpose, different nanosized dendrimer-based drug and gene delivery systems and the interactions between dendrimers and guest molecules have been reviewed. Dendrimers as drug and gene carriers enhance the systemic blood circulation time, biocompatibility, and reduce toxicity. While, on one hand, non-covalent interactions of dendrimer-drug (physical encapsulation) improves drug solubility, on the other hand, electrostatic interactions with charged molecule encourages endosomal escape. Covalent association through various physiologically labile bonds or cleavable linkers can achieve controlled release and targeted delivery of the therapeutic moiety. Dendrimers can act as versatile tools for delivery of nucleic acids, drugs, vaccines for different diseases via different administration routes.

Dendrimer-Based Drug Delivery Systems for Brain Targeting.

Human neuroscience has made remarkable progress in understanding basic aspects of functional organization; it is a renowned fact that the blood–brain barrier (BBB) impedes the permeation and access of most drugs to central nervous system (CNS) and that many neurological diseases remain undertreated. Therefore, a number of nanocarriers have been designed over the past few decades to deliver drugs to the brain. Among these nanomaterials, dendrimers have procured an enormous attention from scholars because of their nanoscale uniform size, ease of multi-functionalization, and available internal cavities. As hyper-branched 3D macromolecules, dendrimers can be maneuvered to transport diverse therapeutic agents, incorporating small molecules, peptides, and genes; diminishing their cytotoxicity; and improving their efficacy. Herein, the present review will give exhaustive details of extensive researches in the field of dendrimer-based vehicles to deliver drugs through the BBB in a secure and effectual manner. It is also a souvenir in commemorating Donald A. Tomalia on his 80th birthday.

All-atomistic molecular dynamics (AA-MD) studies and pharmacokinetic performance of PAMAM-dendrimer-furosemide delivery systems

Improvement of problematic dissolution and solubility properties of a model drug, furosemide, was investigated for poly(amidoamine) (PAMAM) dendrimer complexes of the drug. Full and half generation dendrimers with amino and ester terminals respectively, were studied. In vitro release performance of these complexes was investigated at drug loads ranging 5–60% using simulated gastric fluids. Full generation dendrimers accommodated higher drug loads, outperformed half-generation complexes, and free drug. Pharmacokinetic studies in rats indicated that the dendrimer complexes markedly improved in the bioavailability of the drug compared to the unformulated drug. The G3.0-PAMAM dendrimer complex showed a two-fold increase in Cmax and a 1.75-fold increase in AUC over the free drug. Additionally, Tmax was shortened from approximately 25 to 20 min. One of the first all-atomistic molecular dynamics (AA-MD) simulation studies was performed to evaluate low-generation dendrimer-drug complexes as well as its pharmacokinetic performance. AA-MD provided insight into the intermolecular interactions that take place between the dendrimer and drug. It is suggested that the dendrimer not only encapsulates the drug, but can also orientate the drug in stabilized dispersion to prevent drug clustering which could impact release and bioavailability negatively. AA-MD can be a useful tool to develop dendrimer-based drug delivery systems.

Quantitative interpretation of PAMAM dendrimers adsorption on silica surface

Understanding the dendrimer-solid support interaction is of great importance for dendrimer-based drug delivery system design. The maximum surface coverage on a hydrophilic silica surface was determined using the quartz crystal microbalance with dissipation monitoring (QCM-D) and multi-parametric surface plasmon resonance (MP-SPR) methods: the adsorption process depends on ionic strength and pH of solutions. The effectiveness of G6 adsorption is mainly determined by the range of electrostatic inter-dendrimer interactions and dendrimer-silica surface interactions. Changes in ionic strength have a strong effect on the binding affinity of dendrimers to the surface. The trends in the binding affinity and the surface saturation amount correspond well with the degree of change of protonation of the adsorbed molecules. The development of new research techniques makes it possible to attain a more profound understanding of the self-assembling behaviour of dendrimers. The comparison of QCM-D and MP-SPR allowed the estimation that the dendrimer film contains approximately 70% water. These results indicate that 6th generation PAMAM dendrimers form very hydrated films on silica surfaces. In this case the number of water molecules associated per dendrimer molecule varied from 10,450 to 9,200. The hydration of dendrimer films seems to be a crucial aspect of their implementation. This data confirmed that dendrimers are very promising candidates for many biological applications.

Beware of phosphate: evidence of specific dendrimer-phosphate interactions.

Dendrimers are extensively studied for drug delivery and catalysis, most of which are pH dependent. Phosphate buffer solutions (PBSs) are often used to adjust the pH. We have found that phosphate ions become incorporated into poly(amidoamine) (PAMAM) dendrimer molecules by forming H-bonds with tertiary nitrogens. We show that this specific interaction between H2PO4- and HPO42- ions and generation five PAMAM dendrimers causes a decrease in hydrodynamic size, disturbing the outcome of the size exclusion chromatography analysis. We monitored this interaction by 1H and 31P high resolution NMR, NMR-diffusiometry, pH-potentiometry and infrared spectroscopy. Failing to take into account this effect may lead to incorrect conclusions and misinterpreting interactions of PAMAM dendrimers with drug molecules and subsequently incorrect dosing. The phosphate salts of amino terminated generation five PAMAM dendrimers are stable for years when stored in the dark, even in dilute aqueous solutions, which has important implications for the shelf-life of dendrimer-based drug delivery systems.

Effective targeting of gemcitabine to pancreatic cancer through PEG-cored Flt-1 antibody-conjugated dendrimers

Tumor-targeted delivery of anticancer drugs using dendrimers has been recognized as a promising strategy to increase efficiency and reduce adverse effects of chemotherapy. Herein, we developed a dendrimer-based drug delivery system targeting Flt-1 (a receptor for vascular endothelial growth factors (VEGF)) receptor to improve therapeutic efficacy of gemcitabine in pancreatic cancer. Synthesized polyethylene glycol (PEG)-cored PAMAM dendrimers, which bear anionic carboxylic acid groups on the surface were modified with PEG chains, which were then conjugated with Flt-1 antibody. Following structural and chemical characterization studies, gemcitabine HCl-dendrimer inclusion complexes were successfully prepared. These complexes were efficiently engulfed by Flt-1 expressing pancreatic cancer cells, which enhanced the cytotoxicity of gemcitabine. Moreover, pancreatic tumors established in mice were highly targeted by PEG-cored Flt-1 antibody-conjugated dendrimers and increased accumulation of these gemcitabine-loaded complexes exhibited satisfactory in vivo anti-cancer efficacy. In conclusion, dendrimer-based targeted delivery of chemotherapeutics may serve as a promising approach for the treatment of malignancies such as pancreatic cancer that do not benefit from conventional chemotherapy.

Binding and conformation of dendrimer-based drug delivery systems: a molecular dynamics study

All atomistic molecular dynamics simulations were performed on poly (amidoamine) (PAMAM) dendrimers that compound non-covalently with anticancer drug molecules including DOX, MTX, CE6, and SN38. The binding energies as well as their associated interaction energies and deformation energies were combined to evaluate the relative binding strength among drug, PAMAM, and PEG chains. We find that the deformation of dendrimers due to drug loading plays a crucial role in the drug binding. It is energetically favorable for the drug molecules to bind with PAMAM while the drugs bind with PEG metastable chains via kinetic confinement. Surface PEGylation helps dendrimers to accommodate more drug molecules with greater strength without inducing too much expansion. This work indicates that tuning the functionalized terminal groups of dendrimers is critical to design efficient dendrimer-based drug delivery systems.

Evaluation of polyamidoamine dendrimers as potential carriers for quercetin, a versatile flavonoid

The aim of the present research work was to investigate the potential of polyamidoamine (PAMAM) dendrimers as oral drug delivery carriers for quercetin, a Biopharmaceutical Classification System (BCS) class II molecule. The aqueous solubility of quercetin was investigated in different generations of dendrimers, i.e. G0, G1, G2 and G3, with varying concentrations (0.1, 0.5, 1, 2 and 4 µM). Then, it was successfully incorporated in PAMAM dendrimers and they were characterized for incorporation efficacy, nature of nanoformulations, size, size distribution, surface morphology and stability. In vitro release characteristics of quercetin from all quercetin-PAMAM complexes were studied at 37 °C in phosphate buffer saline (PBS; pH 7.4). Furthermore, the efficacy of quercetin-loaded PAMAM dendrimer was assessed by pharmacodynamic experiment, namely, a carrageenan-induced paw edema model to evaluate the acute activity of this nanocarrier in response to inflammation. It was observed that both generation and the respective concentrations of PAMAM dendrimers showed potential positive effects on solubility enhancement of quercetin. All the quercetin-PAMAM complexes were found to be in nanometeric range (<100 nm) with narrow polydispersity index. In vitro study revealed a biphasic release pattern of quercetin which was characterized by an initial faster release followed by sustained release phase and pharmacodynamic study provided the preliminary proof of concept about the potential of quercetin-PAMAM complexes. The study concludes that the dendrimer-based drug delivery system for quercetin has enormous potential to resolve the drug delivery issues associated with it.

Impact of Dendrimer Surface Functional Groups on the Release of Doxorubicin from Dendrimer Carriers

Generation 5 (G5) poly(amidoamine) dendrimers with acetyl (G5.NHAc), glycidol hydroxyl (G5.NGlyOH), and succinamic acid (G5.SAH) terminal groups were used to physically encapsulate an anticancer drug doxorubicin (DOX). Both UV-vis spectroscopy and multiple NMR techniques including one-dimensional NMR and two-dimensional NMR were applied to investigate the interactions between different dendrimers and DOX. The influence of the surface functional groups of G5 dendrimers on the DOX encapsulation, release kinetics, and cancer cell inhibition effect was investigated. We show that all three types of dendrimers are able to effectively encapsulate DOX and display therapeutic inhibition effect to cancer cells, which is solely associated with the loaded DOX. The relatively stronger interactions of G5.NHAc or G5.NGlyOH dendrimers with DOX than that of G5.SAH dendrimers with DOX demonstrated by NMR techniques correlate well with the slow release rate of DOX from G5.NHAc/DOX or G5.NGlyOH/DOX complexes. In contrast, the demonstrated weak interaction between G5.SAH and DOX causes a fast release of DOX, suggesting that the G5.SAH/DOX complex may not be a proper option for further in vivo research. Our findings suggest that the dendrimer surface functional groups are crucial for further design of multifunctional dendrimer-based drug delivery systems for various biomedical applications.

PEGylated polylysine dendrimers increase lymphatic exposure to doxorubicin when compared to PEGylated liposomal and solution formulations of doxorubicin

Improved delivery of chemotherapeutic drugs to the lymphatic system has the potential to augment outcomes for cancer therapy by enhancing activity against lymph node metastases. Uptake of small molecule chemotherapeutics into the lymphatic system, however, is limited. Nano-sized drug carriers have the potential to promote access to the lymphatics, but to this point, this has not been examined in detail. The current study therefore evaluated the lymphatic exposure of doxorubicin after subcutaneous and intravenous administration as a simple solution formulation or when formulated as a doxorubicin loaded PEGylated poly-lysine dendrimer (hydrodynamic diameter 12nm), a PEGylated liposome (100nm) and various pluronic micellar formulations (~5nm) to thoracic lymph duct cannulated rats. Plasma and lymph pharmacokinetics were analysed by compartmental pharmacokinetic modelling in S-ADAPT, and Berkeley Madonna software was used to predict the lymphatic exposure of doxorubicin over an extended period of time. The micelle formulations displayed poor in vivo stability, resulting in doxorubicin profiles that were similar to that observed after administration of the doxorubicin solution formulation. In contrast, the dendrimer formulation significantly increased the recovery of doxorubicin in the thoracic lymph after both intravenous and subcutaneous dosing when compared to the solution or micellar formulation. Dendrimer-doxorubicin also resulted in increases in lymphatic doxorubicin concentrations when compared to the liposome formulation, although liposomal doxorubicin did increase lymphatic transport when compared to the solution formulation. Specifically, the dendrimer formulation increased the recovery of doxorubicin in the lymph up to 30h post dose by up to 685 fold and 3.7 fold when compared to the solution and liposomal formulations respectively. Using the compartmental model to predict lymphatic exposure to longer time periods suggested that doxorubicin exposure to the lymphatic system would ultimately be 9796 times and 6.1 times greater after administration of dendrimer doxorubicin when compared to the solution and liposome formulations respectively. The recovery of doxorubicin in the sentinel lymph nodes draining the subcutaneous injection site was also quantified directly, and consistent with the lymph pharmacokinetic data, lymph node recovery was greatest for the dendrimer formulation (12% of dosed doxorubicin/g node) when compared to the liposome (1.4%/g node) and solution (<1%/g node) formulations. The data suggest that dendrimer-based drug delivery systems have the potential to enhance drug exposure to lymph-based drug targets such as lymphatic metastases.

Pulmonary Administration of PEGylated Polylysine Dendrimers: Absorption from the Lung versus Retention within the Lung Is Highly Size-Dependent

The systemic delivery of drugs via the inhaled route is an attractive, needle-free means of improving the systemic exposure of molecules such as peptides and proteins that are poorly absorbed after oral administration. Directed delivery into the lungs also provides a means of increasing drug concentrations at the site of action for lung-specific disease states such as pulmonary infections and lung cancer. The current study has examined the potential utility of PEGylated polylysine dendrimers as pulmonary delivery agents and in particular sought to explore the relationship between dendrimer size and absorption of the intact construct (as a potential systemic delivery mechanism) versus retention within the lungs (as a potential pulmonary depot for controlled local release). Dendrimer absorption from the lungs was inversely correlated with molecular weight, with approximately 20-30% of the dose of relatively small (<22 kDa) dendrimers systemically absorbed compared to only 2% absorption for a larger (78 kDa) PEGylated dendrimer. Increasing the molecular weight of the dendrimers led to slower absorption and more prolonged retention in the lung tissue and bronchoalveolar lavage fluid. Oral administration of the two smaller dendrimers confirmed that oral bioavailability of the PEGylated dendrimers was essentially zero and did not contribute to exposure after pulmonary administration. The smaller PEGylated dendrimers were also degraded in the lungs to low molecular weight products that were subsequently absorbed and excreted via the urine, while the larger constructs showed good stability in the lungs. The data suggest first, that small PEGylated dendrimer-based drug delivery systems may be delivered to the blood via inhalation, providing a more attractive alternative to injections, and second that larger PEGylated dendrimers may be retained in the lungs providing the potential for controlled delivery of medications to the blood or lung tissue.

Dendrimer‐Based Drug Delivery Systems: From Theory to Practice. Edited by Yiyun Cheng

Book review: “Dendrimer-based drug delivery systems: from theory to practice”, Edited by Yiyun Cheng, foreword by Donald A. Tomalia

Fast Screening of Dendrimer-Binding Compounds by Diffusion NMR Techniques

High-throughput screening of dendrimer-binding drugs is essential for the design and optimization of dendrimer-based drug delivery systems. In this study, pulsed gradient spin echo (PGSE) NMR was used for fast screening dendrimer-binding compounds using common amino acids as a screening pool. Diffusion coefficients of the amino acids before and after the addition of poly(propylene imine) (PPI) dendrimer were used to rank the binding affinities of the amino acids to the dendrimer. Among the common amino acids, cysteine, glutamic acid, aspartic acid, and tryptophan show strong binding affinity to PPI dendrimer. Tryptophan forms inclusion complexes with PPI dendrimer through hydrophobic interactions, while other amino acids mainly bind with PPI dendrimer via ionic and hydrogen-bond interactions. The PGSE NMR-based screening method provides new insights into high-throughput screening of dendrimer-binding compounds and should facilitate the study of dendrimer-based host-guest systems.