Insights on the Dynamic Innovative Tumor Targeted-Nanoparticles-Based Drug Delivery Systems Activation Techniques

Abstract

Anti-cancer conventional chemotherapeutic drugs novel formula progress, nowadays, uses nano technology for targeted drug delivery, specifically tailored to overcome therapeutic agents' delivery challenges. Polymer drug delivery systems (DDS) play a crucial role in minimizing off-target side effects arising when using standard cytotoxic drugs. Using nano-formula for targeted localized action, permits using larger effective cytotoxic doses on a single special spot, that can seriously cause harm if it was administered systemically. Therefore, various nanoparticles (NPs) specifically have attached groups for targeting capabilities, not seen in bulk materials, which then need activation. In this review, we will present a simple innovative, illustrative, in a cartoon-way, enumeration of NP anti-cancer drug targeting delivery system activation-types. Area(s) covered in this review are the mechanisms of various NP activation techniques.

Keywords: DDS; NPs; cancer biology; drug delivery systems; extrinsic-activation; intrinsic-activation; nano-bio-medicine; nanoparticles.

Graphical abstract

Figure 1

Anti-cancer drug NPs delivery to the tumor target site (A) localization/targeting, (B) intrinsic-activation where healthy cell (poor man) lacks certain feature(s) (money) and tumor cell (rich man) has plenty of these feature(s), (C) extrinsic-activation where the tumor (house) is vulnerable to external factors (humor) effect). Where the anti-cancer drug (boy) is surfing to the target receptor site destination (island), carried over a nanocarrier (NC) (floating board) and functionalized by a ligand (rope) that might be an antibody, aptamer or peptide (A). Taking in mind that cancerous cells are more acidic, higher certain enzymes levels and concentration of certain substances or different in certain features due to an altered tumor cell metabolism and/or different gene expression level, arising from an uncontrolled cell division (money with the rich), from healthy cells (poor man) (B). Extrinsic activation factors (like a hammer) from outside the tumor cell (wooden house), where this(ese) external effect(s) as ultrasound, X-ray and light, is/are applied to kill cancerous cells (wooden house) (C).

Figure 2

pH-dependent activation (A) organ-specific release, (B) tissue-specific release, (C) cell-specific release. Nano-systems can be constructed where changes in acidity triggers drug release from its nano-formula, from pH differences between healthy and malignant cells that can result in organ-specific release, tissue-specific release or cell-specific release. Using pH activated NPs (thief) protects the cargo (drug in bag), controlling its release, mainly, at the target ileum site. Indeed, it seems like hiding the drug (bag) to escape the stomach acidic pH (policeman) (A). Nano micelle encapsulating anti-cancer drugs and containing two peptides on its surface with AIE moiety, (B), to monitor and induce apoptosis. This system only collapses and releases the cytotoxic drug to the tumor site at low pH. Acidic pH level difference will provide a good environment for localizing drug release from pH-sensitive nanomaterials that act as a body guard (Spike the dog) to protect their cargo (Jerry the mouse) from lysosomal enzymes (Tom the cat) as RNA interference (RNAi) which is a lysosome-sensitive cargo. An α-cyclodextrin nano-valves complexed with an aniline-based stalk on the surface within MSNs (C) left, after entering the tumor cell, the lysosomal acidic pH activates these nanovesicles by weakening the link between the stalk and the cyclodextrin, allowing the anti-cancer drug release (C) right.

Figure 3

Endogenous enzyme-dependent-activation of anti-cancer NPs, leading to anti-cancer drug (cheese) release at the tumor target site when the substrate (rat) is cling to trap (enzyme) (A), activation by telomerase (hand) (B) to release anti-cancer drug (Dox) like peeling a banana released after extending 3’ aptamer end (banana peel) which is overexpressed in tumor cells. When conjugating a chemotherapeutic drug to the enzyme substrate, then activation occurs massively at the tumor site, where the enzyme is located there, with minimal side effects to normal cells. This is like the rat holding cheese (substrate attached to the anti-cancer drug) is directed toward the overexpressed enzymes (trap) and release the free drug, thus specific targeting is achieved (A).

Figure 4

Hypoxia-activation of anti-cancer prodrug by glucose oxidase enzyme-loaded NPs. Hypoxic tumor condition induced by glucose oxidase will activate the chemotherapeutic AQ4N prodrug (A). Now, the glucose oxidase (hand) removes the oxygen mask (oxygen environment surrounding drug) generating a hypoxic condition which activates the chemotherapeutic prodrug (the stable not swimming diver boy) after mask removal the diver try to swim and moves quickly (active drug) as illustrated in (B).

Figure 5

Concentration-dependent intrinsic-activation of anti-cancer drugs NPs (A) overexpression of the membrane protein TfR (taxi) on tumor cells surface (garage target destination) carrying anti-cancer drug and iron (B) high conc. soluble molecule as GSH results in silica-based NPs disintegration. High GSH concentration cause degradable dendritic mesoporous organo-silica NP (DDMON) disintegration via reducing the disulphide bond, together with the therapeutic drug release, with high selectivity to cancerous cells. High GSH concentration is like the fire that causes the bomb explosion (DDMON) and release what is inside (the anti-cancer drug money bags) (B).

Figure 6

Ultrasound extrinsic-activation of anti-cancer NPs by (A) microbubbles stable cavitation, (B) Piezoelectric nanomaterials mechanism on altering electrical potential of cancer cells. Delivery of Dox or paclitaxel released directly after applying ultrasound and shell rupture. Ultrasound applied on microbubbles (iron balls) causes streaming of fluids in tumor tissue that perforate the cell membrane (boat) so facilitate drug entry (fountain) (A). (B), where disturbance in the traffic lights leads to car accidents, presenting electrical energy generated via changing potassium and calcium levels and hence, potential difference to disrupt cell division causing cancer cell death.

Figure 7

Magnetic field activation: (A) magnetically-induced hyperthermia where IONPs extrinsic-activation convert alternating magnetic energy to heat energy that acts as a fire to melt tumor cells (like an ice cream left outside the fridge), (B) IONPs squeeze the cationic liposomes (egg rupture) under the action of permanent magnetic field (force) leading to drug release (chick), (C) following smart stimulus nano systems IONPs allow or prevent drug entry according to the magnetic field direction. IONPs movement as a pore blocking system where it moves in certain direction to allow drug release and moves in the other direction to prevent drug release according to the direction of alternating magnetic field, as a window opened or closed to allow sunlight entry according to the direction of the wind. “Super paramagnetism” using alternating magnetic field leads to an increase in local temperature up to 42°C causing cell death.

Figure 8

Photodynamic therapy extrinsic light-activation using up-conversion NPs. Light energy (playing stick) activates up-conversion NPs (white ball) that activates the photosensitiser (orange/white ball) giving ROS to kill cancer cells (going into the goal pocket).