Drug Delivery.

History of controlled drug delivery systems.

The acquisition and development of knowledge on how drugs exert their pharmacological

effect, mainly information such as dose-response onset and pharmacodynamics and

pharmacokinetic relationships, has demanded attention to stimulated interest in delivering drugs

at rates and locations that optimize their effects. Controlling drug release has accordingly

evolved as a multidisciplinary science in conjunction with innovations in different disciplines

such as polymer chemistry.1 Over the last two centuries, controlled drug delivery technology has

significantly advanced, leading to various clinical formulations. Controlled drug delivery

systems are inevitable as a drug will not be significant without a suitable delivery system

determined by its physicochemical properties, selecting the type of delivery medium, and the

discharge mechanism. A controlled drug delivery system results in improved efficacy, reduced

toxicity, patients' compliance, convenience, and enhanced drug therapy effectiveness.

The first production of controlled drug delivery systems recorded in 1950-1980 concentrated on

formulating oral and transcutaneous sustained release systems. This system was designed by

Smith Kline $ French in 1952 for twelve-hour Dexedrine delivery. Until the end of the 1970s, the

basic concept of controlled drug delivery was validated. This concept contained differentiated

drug discharge mechanisms such as dissolution, diffusion, osmosis, and ion-based tools. The

second-generation controlled delivery system was focused on maintaining a steady drug

concentration in the blood. However, they realized that maintaining a constant concentration in

the blood was unnecessary as most drugs' efficacy remains constant as long as the drug

concentration is above the minimum adequate level and below the maximum safe concentration

(fig1). Biodegradable molecules, solid implants, and in situ-gel forming were also developed and

used in the delivery of proteins and peptides. The Nano era again kicked off in this generation,
where smart polymers and hydrogels were designed for manufacturing delivery systems

activated by natural factors such as PH, temperature changes, and glucose level. The second

generation focused on the development of nanotechnology delivery systems. Although the third

generation is yet to be authenticated, (table1) shows the possible outcome as predicted compared

to the existing drug delivery systems.

Figure 1.
The drug is productive provided that its blood concentration is above the minimum productive
concentration regardless of its pharmacokinetics. (This is based on the assumption that the maximum
concentration of the drug does not exceed its toxic level)

Commercial Challenges of Protein Drug Delivery

 Most protein drugs are dispensed through injections and require daily and weekly

injections. A majority of these are only useful in low doses. Manufactures of protein

drugs are limited because they have to consider peptides and compounds that have no

dangerous side effects when administered in high doses. Innovative companies have to

undergo extensive processes to get marketing approval for their products. This was

evident in 2004 when the Exuberant product was submitted for marketing approval in

March. It wasn't until August that the European Medicines Evaluation Agency deemed it

not licensable. The Exuberant product was inhaled insulin which would be an effective

alternative.

As Larry Brown puts it, "polymeric-based sustained-release technology has been very much

constrained to low-molecular-weight peptides rather than large therapeutic protein molecules"2.

The development of these small molecules is very complex and costly, limiting the number of

protein drugs that can be delivered. Their small sizes make non-invasive methods the best for

their delivery. However, this is made impossible by the low bioavailability of the peptides. These

small-molecule protein drugs are also easily denatured by heat and are usually vulnerable to

chemical and physical degradation. Pegylating and glycosylation of proteins and peptides is an

alternative that could be a solution to their low bioavailability. Glycosylation, in particular,

increases biological half-life in humans, which could allow administration of larger doses.2

However, this method faces various challenges. The chemistry used to make these chemical

alterations has to be compatible with all kinds of proteins. There can also be demurs in

determining the exact tracts of conjugation in polypeptides.2 The delivery system of protein

drugs is a complex process that is still in need of improvement.

 Table 1

Engineered polymers for advanced drug delivery

Engineered polymers have been employed in the development of advanced drug delivery

systems; smart polymers. Originally, polymers were applied as additives to dissolve and

reinforce drugs or as mechanical supporters for drugs' steady release. Input from fields in

particular biochemistry and nanotechnology has made polymers and their drug delivery systems

smarter and more productive. Stimuli-sensitive polymers, which exhibit operational

responsiveness to environmental and physicochemical changes, are designed.3 Signals such as;

physical temperature, ultrasound, light, electricity, mechanical stress, chemical PH, ionic, and

biological enzymes are either externally supported or internally by the pathophysiological

condition.

The smart polymer's most fascinating features occur as a result of the versatility and tunable

sensitivity. Countless monomers show reactiveness to specific stimuli. Each monomer can be
tuned to a homopolymer reacting to one signal and copolymers reacting to multiple stimuli.

Hence, this makes smart polymer systems more authentic and programmable drug delivery. An

example is a thermosensitive polymer that originates from the equilibrium between hydrophobic

and hydrophilic segments, both as monomer fragments or polymer hunks. Figure 2 is a summary

of the development of a controlled delivery system for clinical formulations.

Chemistry as a Tool for Cell Engineering and Drug Delivery.

Click chemistry is applied in cell engineering and drug delivery system to diagnose and treat

diseases. The combination of metabolic glycol engineering and click chemistry is a powerful

mechanism for the surface alteration method for cell functionalization in cell-based sciences and

engineering. Koo et al. developed the cell gluing technique based on the IEDDA reaction (fig3)4.

The chemically combined cells withstood a high stress level; moreover, with endovenous

injection of the glued cells, they survived and maintained their structures of two or more cell
pairs in the bloodstream. Hence IEDDA reactions can successfully maintain a stable cell-cell

adhesion in a short amount of time.

Copper-free has been implemented in drug delivery to diagnose and treat diseases as a

useful substance target since it has high specificity, high rate of reaction, and stability. Through

the SPAAC reaction and biorthogonal chemical receptors, tumor cells can be attacked by DBCO

modified drugs. The SPAAC reaction is useful for drug delivery for cancer cell-specific imaging.

Scheme1 shows the reaction rates.

A; CuAAC reaction with azide and linear alkyne5

B; SPAAC reaction with azide and cyclooctyne6
C; IEDDA reaction with Tz and TCO7

Delivery System for Breast Cancer Treatment

Breast cancer is cancer that affects both the female and the male but rampant in females. It falls

second in the most diagnosed cancers following skin cancer and has a high mortality rate. It is

caused by abnormal growth of breast cells. Chemotherapy and radiotherapy applied in the

treatment can cause biological side effects, hence needing a drug delivery system to decrease

side effects. Nanoparticles are one of the substances used to reduce toxicity. Polymers being
tunable and useful in different ways of drug release are highly adopted in drug delivery systems

by using varying polymerization methods, such as dispersion, emulsion, and precipitation

polymerization.

Several experiments have been carried out to develop a polymer-based delivery system for

breast cancer treatments. This includes; 5fu-coated magnetic imprinted polymer by Hashemi-

Moghaddan 2015, imprinted AZT by Hassapour 2019. Fluorescence magnetic carrier has fast

kinetic adsorption, high adsorption capacity high affinity towards the 5Fu due to the effective

imprinting process. 5u is an antimetabolite and hydrophilic chemotherapy agent used as an

anticancer for gastrointestinal and breast cancer treatment. As a result of its high metabolism

rate, a large dosage is needed thereby increased chances of side effects.8 This means the need for

a selective drug carrier.

Nanotechnology aims to maximize the efficacy of the drug used in cancer treatment and

minimize the possible side effects; hence it has adopted chitosan hydrogel as a targeted drug

delivery system. Chitosan hydrogen network is made up of three different cross-linking agents

soaked in water. Thermosensitive, PH sensitive, photosensitive, and dual sensitive hydrogels

change from solutions to gel once injected through the construction of the 3-dimensional

network. This construction can be achieved either by chemical or physical cross-linking

triggered by external stimuli. The amount and the rate of absorption are steered by cross-linking

density, the polymers' chemical structure, and the environmental conditions. Crosslinkers

determine the physical strength. Through physical or chemical cross-linking, chitosan can be

integrated into various forms including powder.

Barriers to Drug Delivery

 Barriers hinder the successful accumulation of Nanotherapeutics specifically at diseased

tracts inhibiting valuable responses in illnesses varying from cancer to inflammation.9 These

barriers to the transport of drugs are either biological, physiological, or chemical. They include;

Paracellular pathway; this pathway exists to prevent toxins, bacteria, and viruses from entering

into the basolateral side and selectively allows the passage of molecules and cells. Another

limiting factor is the transcellular pathway. Provided a drug has the right physiochemical

characteristics, it should traverse through the cell by diffusion. However, this is a limiting factor

to medicines such as peptidomimetics which travel through the lipid bilayers as they lack the

chemical properties to facilitate distribution.

Nano therapeutic delivery fails to attain the reparative levels of drugs at disease sites due to

inexact ingestion of Nanoparticles in healthy organs. Nanoparticles attach to specific receptors

on phagocytes' surface; they are thereafter internalized, transported to phagosomes, and later

fused with lysosomes. This sequestration by the mononuclear Nanoparticle is a limiting factor to

successful drug delivery. Homorpheology and blood vessel fluid dynamics is also a chemical

barrier for drug delivery. The size and geometry of the model is a determiner of Nanoparticle

fluid elements in blood vessels. Liposomes and polymers, for example, are explicitly designed

for intravenous delivery, following their spherical geometry.

Contrary to the spherical drugs, non-spherical drugs are more susceptible to tumbling and

oscillatory effects in vasculatures, raising the Nanoparticle cell contact and potential

extravasation highly through vasculature fenestrations. These Nanoparticles include those

possessing discoidal geometry. Moreover, the spherical drugs can also cause tumor amassing and

active targeting strategies as they lower the number of binding and contact pants while in contact

with endothelial cells.

 Additionally, intratumoral pressure and Nanoparticles can also hinder the transportation of

drugs. A typical vasculature has tight inter-endothelial seams that prevent the particles' leaking

into the tissues. An imbalance of various factors affects the size of fenestrations in tumor

vasculature. An example is nitric oxide which increases the gap in the endothelia. The dense

extracellular matrix in the tumors prevents Nano particles' adequate penetration into the tumor

limiting drug delivery. Aside from the barriers mentioned above, Nanoparticles gene therapies

face genetic material instability challenges, such as MRNAs, antisense, alogonuclotides, and

siRNAs.

Nevertheless, research efforts have born multiple performances and components within the

Nanoparticle design to address these barriers. One of the modifications employed is modified

drug entities. A prodrug approach has been utilized to optimize drugs that improve the

absorption of an oral drug or site-specific delivery. Furthermore, formulations have been adopted

to enhance permeation through biological barriers. Drugs such as peptide absorption are

enhanced by optimal formulation.

Nanoparticle flow, margination, and adhesive properties in blood vessels are dependent on particle size

and geometry. (a) Unlike spherical nanoparticles, no spherical particles, such as those possessing

discoidal geometries, are more prone to tumbling and oscillatory effects in the vasculature, increasing

the propensity of nanoparticle–cell wall contact and potential extravasation through fenestrations in the

vasculature considerably. (b, c) Once in contact with endothelial cells, the small size and surface area of

conventional spherical nanoparticles (b) reduce the number of binding and contact points compared
with larger, discoidal nanoparticles (c; as well as other non-spherical geometries), which can affect

tumor accumulation and active targeting strategies

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