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Book condition: NEW Quantity available: 5. Despite some excellent drugs are available, the efficacy of many existing chemotherapeutics is limited by their inability to reach their therapeutic site of action in sufficient amounts to be effective [ 20 ]. In most cases, patients are administered with an excess of medications that are distributed throughout the whole body, and thus, it is extremely difficult to avoid distribution into healthy organs and tissues and the depression of the immune system.

It always gives the limitation of dosage that can be given and, in turn, prevents these drugs from achieving the potential cures [ 21 ].

PDF – Drug Delivery: Fundamentals and Applications, Second Edition # 7105

Current anticancer drugs often have a poor therapeutic index and they cause a lot of side effects [ 22 ]. A major concern is when the medications affect non-cancer cells, causing the adverse reduction of red and white blood cells, and affecting the gastrointestinal tract triggering nausea and diarrhea [ 23 ].

To reduce, or even better to avoid such side effects, the drug delivery to the tumor is optimized by preparing carriers containing an active agent associated with a molecule capable to accurately target cancer cells such as antibody drug conjugates ADC or nanoparticles [ 24 — 26 ]. Dendrimers have been engineered as nanodevices, either in nanocarrier drug approaches or as drugs per se.

The biological effect of dendrimers is caused by terminal moieties and is responsible for the global efficiency. Dendrimers due to their proper, reproducible, and optimized design parameters overcoming the physicochemical limitations of classical drugs for example, solubility, specificity, stability, biodistribution, and therapeutic efficiency are successful. They are also able to omit biological problems to reach the right targets such as first-pass effect, immune clearance, cell penetration, and off-target interactions [ 27 ].

Polymers are commonly used materials for nanoparticles-based delivery [ 28 ], among them dendrimers are the ones more commonly used as a non-viral delivery system. The best drug carrier should meet several requirements such as drug retention, release the drug, unaffecting by the immune system, extending the time in blood circulation, and specific targeting to cells or organs [ 29 ]. When a drug carrier is applied to the patient and reaches the level of the blood, it starts an intricate trip before it is able to reach the destination of the target site.

When they attach to the target cell membrane, they undergo the endocytosis process. There are several parameters of dendrimers that can facilitate the process.

Nanotechnology in Drug Delivery: Fundamentals, Design, and Applications

We have to emphasize also the impact of the body structure including size, shape, additional chemistry on the surface, and mechanical flexibility [ 30 ]. The nanoparticles, due to their size, have a huge impact on the circulation time if they are applied intravenously IV , so they are safe for the smallest capillaries and they are not able to clog them [ 31 ]. Cellular uptake by phagocytosis and endocytosis is also particle size dependent [ 32 , 33 ].

The unique uniformity of dendrimers gives them the ability to cross the membrane of cancer cells. The anticancer drug can be either non-covalently encapsulated in the core of the dendrimer or covalently conjugated to its surface, being possible to customize the drug release profiles by controlled depolarization processes [ 34 , 35 ]. Such a solution helps to solubilize the hydrophobic drugs and leaves the drug unaltered [ 36 ]. The attachment of anticancer drugs to the surface groups of the dendrimer by covalent chemical bonds offers also some other advantages compared to the non-covalent encapsulation.


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Besides the enhancement of solubilization of the drugs, it is possible to attach many different hydrophobic anticancer drugs, and the controlled release is being maintained [ 37 , 38 ]. Dendrimers have already been used as passive anticancer nanocarriers [ 38 — 41 ]. There are preclinical promising results in vitro as well as in vivo with active targeting dendrimers [ 36 ]. For example, antibody-dendrimer conjugates showed better efficacy than free antibodies [ 42 — 45 ]. It has been also reported that dendrimers modified with folic acid on the surface generated better tumor accumulations that untargeted controls or free drug, producing a stronger reduction of the tumor mass [ 46 , 47 ].

Moreover, sugar-modified PPI dendrimers tested by our research team at University of Lodz, Poland, are very attractive and specific for leukemia and lymphoma cells derived from lymphocytes B. Depending on the sugar on the surface and the number of molecules, we can observe the different extend of triggering apoptosis in those cells due to the diversity in affecting particular gene pathways [ 48 — 51 ].

Some of the positively charged dendrimers could even inhibit the growth of amyloid fibrils or even disrupt existing mature of these fibrils.

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Others could decrease the number of toxic amyloid oligomers [ 55 , 56 ]. The slow translation of preclinical studies to clinical trials may be due to the toxicity of dendrimers [ 46 , 47 ], with the aim of the current research in the development of new biocompatible and less toxic alternatives [ 57 , 58 ]. Once these molecular machines arrive at the target site inside the living organism, several barriers must be overcome.

Nanocarriers are usually internalized by endocytic processes [ 59 ], the processes called vesicular internalization. The most widely studied endocytic pathways are clathrin-mediated endocytosis, caveolae-mediated endocytosis, and macropinocytosis, but other cellular pathways have been recently identified, including clathrin- and caveolae-independent endocytosis and phagocytosis [ 60 ].

Nano-Pharmacology and Drug Targeting

Molecules, which are internalized by the cell membrane, are endocytosed by the early endosomes pathway. They may progress later to late endosomes and lysosomes. If the loading of dendrimer targets the nucleus, thus the nuclear membrane is another barrier that the dendrimer should come across [ 61 ]. We should be very careful designing the drug delivery system because unexpectedly our desired nanovector might have its own power. This is what our genetic research has shown—4th generation PPI glycodendrimers with maltotriose molecules directly trigger mechanism of apoptosis in mitochondria of lymphocytes B, particularly those transformed to the leukemic cells.