PH Responsive Tumor Targeted Drug Delivery: Advancing Precision in Cancer Therapy Through Nanomedicine

By Fouad Sabry

PHresponsive tumortargeted drug delivery-The opening chapter introduces the principles of pHresponsive drug delivery systems, focusing on their application in targeting tumor cells with greater precision

Ligandtargeted liposome-This chapter explores the use of ligandtargeted liposomes in delivering drugs to specific tumor sites, offering an efficient strategy for selective drug release

Pullulan bioconjugate-Delving into the innovative use of pullulan bioconjugates, this chapter highlights their role in enhancing the stability and targeting abilities of drug delivery systems

Drug carrier-An overview of drug carriers and their mechanisms, detailing how these carriers improve the bioavailability and therapeutic efficacy of anticancer drugs

Ultrasoundtriggered drug delivery using stimuliresponsive hydrogels-This chapter presents the integration of ultrasound with stimuliresponsive hydrogels, a groundbreaking method to trigger localized drug release at tumor sites

Nanogel-Focuses on nanogels, which are gaining attention as advanced delivery vehicles due to their versatility in drug encapsulation and controlled release

Nanocarrier-Explores various types of nanocarriers, detailing their potential in drug delivery, enhancing the targeting and bioavailability of therapeutic agents

Intravesical drug delivery-Discusses the emerging strategy of intravesical drug delivery, focusing on how it improves local cancer treatment by delivering drugs directly to the bladder

Nanoparticle drug delivery-This chapter reviews the diverse applications of nanoparticles as carriers for targeted drug delivery, emphasizing their potential in improving cancer therapies

Reductionsensitive nanoparticles-Examines nanoparticles that respond to reducing environments within tumors, allowing for controlled drug release at precise locations

Microbubble-Discusses microbubbles, their role in enhancing drug delivery when combined with ultrasound, and their applications in cancer therapy

Stimuliresponsive drug delivery systems-An exploration of various stimuliresponsive systems, including those sensitive to pH, temperature, and light, in optimizing drug delivery efficiency

Aldoxorubicin-This chapter details the use of aldoxorubicin, a drug conjugated to a pHsensitive linker, for targeted drug delivery in cancer treatment

Intranasal drug delivery-Focuses on the potential of intranasal drug delivery as a noninvasive method for targeting tumors, with a special emphasis on brain cancer therapies

Dextran drug delivery systems-Explores dextran as a biocompatible and versatile polymer for drug delivery, particularly in cancer therapy

Arginylglycylaspartic acid-An indepth discussion of Arginylglycylaspartic acid (RGD) peptides and their applications in targeting tumors, enhancing delivery efficiency

Sonodynamic therapy-Reviews sonodynamic therapy, a promising technique combining ultrasound and photosensitive agents for targeted drug delivery in cancer treatment

Anthracycline-Discusses the use of anthracyclines in combination with nanocarriers, improving their therapeutic effect by increasing targeted delivery

Magnetic nanoparticles in drug delivery-This chapter examines the application of magnetic nanoparticles in drug delivery, focusing on their ability to concentrate therapeutic agents at tumor sites using magnetic fields

Immunoliposome therapy-Explores immunoliposomes, combining liposome technology with immune targeting to deliver cancer drugs directly to tumor cells

• Language: English
• Publisher: One Billion Knowledgeable
• Release date: Mar 12, 2025

Book preview

Chapter 1: PH-responsive tumor-targeted drug delivery

Nanoparticles are utilized in a specialized form of targeted drug delivery known as pH-responsive tumor-targeted drug delivery. This type of drug delivery is designed to deliver therapeutic medications directly to cancerous tumor tissue while simultaneously reducing the occurrence of interactions with healthy tissue.  The pharmacokinetics and targeted action of a medicine can be altered by the use of drug delivery, which involves combining the drug with a variety of excipients, drug carriers, and medical devices. This procedure has been utilized by scientists. In order to respond to the pH environment of diseased or malignant tissues, several drug delivery systems have been developed. This reaction causes structural and chemical changes within the drug delivery system. The purpose of this particular method of targeted drug administration is to localize the distribution of the drug, to extend the action of the medicine, and to protect the drug from being broken down or destroyed by the body before it reaches the tumor.

It is important to note that the microenvironment of a tumor is distinct from that of normal, healthy tissues found within the body. It is important to note that the pH levels are different. Tumor tissue has a pH level that ranges from 7.0 to 7.2, which is referred to as tumor acidosis. The human body as a whole has a tendency to have a more alkaline pH level of 7.4. Acidosis of the tumor can be caused by a number of different reasons, including as hypoxia, the Warburg effect, and the generation of acidic metabolites by the tumor cells themselves.

The condition known as tumor hypoxia takes place when the environment surrounding a tumor has oxygen levels that are low or significantly depleted in comparison to healthy tissue. This condition can result in tumor acidosis. When tumor cells reproduce at a rapid rate, they expand in size and do not receive an adequate amount of blood supply. According to the findings of certain studies, this causes the surroundings surrounding tumors to become hypoxic, which in turn causes metabolic abnormalities.

The Warburg Effect is the phenomenon in which cancer cells use aerobic glycolysis as their primary method of cell metabolism. This leads to an increased rate of glucose uptake and a preference for lactate generation, despite the presence of oxygen in the oxygen environment. The reason why cancer cells modify their metabolism technique, which is energy inefficient, is still a mystery after all these years. Although this technique is ineffective in making ATP, there are studies that suggest that cancer cells may be employing aerobic glycolysis to generate energy. This is due to the fact that aerobic glycolysis is a faster process than the typical process of respiration. Through this process, these cancerous cells are able to generate energy in a short amount of time. One situation in which they are required to rapidly develop and divide is one in which this is especially important. Because of an excessive amount of lactate synthesis, an accumulation of acidic metabolites takes place.

Consequently, the targeting of the acidic microenvironment of tumors has emerged as a potentially effective technique for the treatment of cancer disease. Creating drug delivery carriers that are sensitive to pH levels and have triggered drug release at the tumor site is one strategy that can be taken. This approach has the potential to improve the effectiveness of chemotherapy and other therapies.

It is possible to detect changes in the pH levels within the body through the use of pH-responsive tumor-targeted medication delivery. These polymer drug carriers transport the therapeutic medications in order to facilitate the delivery of drugs in a targeted manner. Without activating and releasing the medication in healthy tissue, the pH-triggered drug release is designed to deliver the drug exactly to the location of the tumor. This is done in order to achieve the desired effect. The complex is comprised of a drug delivery unit that is composed of a carrier molecule that is composed of anti-tumor medicines, organic nanomaterials, inorganic nanomaterials, and composite nanomaterials. As a result of the carrier's ability to compromise pH-sensitive molecules, the drug vehicle is able to activate at the tumor site within the appropriate pH range that it is designed to function at in order to release the medication.

It is possible to divide the process of loading anti-tumor medications into pH-responsive polymer nanoparticles into three distinct categories: chemical bonding, intermolecular force, and physical encapsulation. Through the utilization of these loading processes, the medicine is able to remain contained within the carrier until it reaches the environment of the tumor. At the same time, the carrier can be developed to have the capability of modifying its structure or properties in reaction to the change in pH. Chemical bonds that hydrolyze or break in acidic environments are examples of common pH-sensitive structures. various examples include polymers that vary their charge properties with changes in pH, as well as various types of pH-responsive polymers. As an illustration, there are two potential methods that may be utilized: the incorporation of protonatable groups or the formation of acid-like bonds. Upon being subjected to the low pH, changes in protonation and ionization that are produced by the pH cause disruptions in the hydrophilic-hydrophobic balance that exists within the nanocarrier. This results in the nanocarrier disassembling, which in turn releases the medicine that was encapsulated within the carrier. The amino, carboxyl, sulfonate, and imidazolyl groups are examples of ionizable groups that are frequently utilized. Drug release from these nanocarriers can take place by precipitation, aggregation, or dissociation mechanisms, depending on the acid dissociation constant (pKa) of the functional group that has been added. Another alternative carrier might be lipid-based, and a decrease in pH can cleave the covalent acid-labile bonds on the surface and within the carrier, which can then lead to swelling of the drug delivery system and the subsequent release of the drug at a predetermined rate.

It has been demonstrated through research that pH-responsive tumor-targeted drug delivery carriers offer a number of benefits. One of the most significant benefits is the enhanced specificity that targets the tumor cells, in addition to the relatively low cytotoxicity that is measured in comparison to other treatment modalities. Due to the tailored approach that this drug delivery system takes, the low toxicity is the consequence of decreasing the exposure of the drug or therapy to healthy tissue rather than the other way around. The efficiency of the drug release rate is another element that was observed during the process of prior investigations.  The anti-cancer medicine is released from the drug carrier when the low pH levels of the tumor are triggered, and the pace of drug release is controlled by the pH levels of the tumor environment. The administration of drugs often necessitates frequent dosing; however, the utilization of a drug delivery carrier enables a slow and prolonged release of the medicine, which in turn reduces the frequency with which cancer patients are required to visit the clinic for treatment purpose.

The formation of hydrogels involves the interconnection of polymer networks, which results in the formation of a three-dimensional structure that is able to absorb and hold significant quantities of fluids. Numerous hydrophilic groups, including -NH2, -OH, -COOH, and -SO3, are present in the polymer chains. When it comes to tumor-targeted drug carriers, hydrogels are rather insoluble unless they are triggered by a change in pH. This is because enhanced capillary activity makes them more insoluble. There are a variety of drug delivery methods, and the physical properties of hydrogels can be modified to fulfill the specific requirements of each of these systems. The development of pH-responsive hydrogels has been considerable in recent years, and these hydrogels have proven to be very useful for the treatment of cancer in specific areas. They are able to extend the duration of drug release, and their synthesis is both speedy and economical.

Over the course of the last ten years, researchers have been focusing their efforts on developing an injectable hydrogel post-resection surgery for the purpose of treating tumor locations. An injectable biomaterial that is made up of polylactide-co-glycolide (PLGA) and polyethylene glycol (PEG) hydrogel is a copolymer that has been approved by the Food and Drug Administration (FDA) for use in therapeutic devices due to its biodegradability and biocompatibility properties in the human body. PLGA and PEG hydrogel are both examples of copolymers. This hydrogel has been loaded with cancer therapy medications for the purpose of providing localized treatment in breast tumors that have undergone surgical excision, according to investigations that have been conducted. Additionally, drug-loaded particles within the hydrogel have been presented as dual-stimuli responsive drug delivery systems. These systems combine the pH-responsivity of the PEGylated polyester gels with the temperature responsiveness of the gels. These kinds of hydrogels have been shown to be effective in treating malignancies in the lungs and bladders, according to studies.

Liposomes are biomimetic nanosomes that are formed of phospholipid bilayers. They were first identified potential drug-delivery vehicles in the 1960s because of their biomimetic properties. When it comes to pH-responsive tumor-targeted drug delivery, liposomes are a popular choice because of their biocompatibility, biodegradability, and the ability to encapsulate both hydrophilic and hydrophobic medicines. It is possible to modify the liposome in order to create conditions that will facilitate triggered release in response to acidic environmental conditions. It is possible to make these by incorporating pH-sensitive components into the process of liposome fabrication. In general, pH-responsive liposomes are made up of amphiphiles that are just slightly acidic, such as cholesteryl hemisuccinate (CHEMS), and cone-shaped lipids, such as dioleoylphosphatidylethanolamine (DOPE). Due to the low hydration of their polar head and the neutralization of the negatively charged phosphodiester groups, DOPE takes on a bilayer structure when it is at a neutral pH. However, when it is exposed to acidic conditions, such as tumor sites, it forms a hexagonal inverted structure. This causes the substance to become destabilized and release its content, while it remains stable at a physiological pH. Liposomes that are sensitive to pH have a number of major benefits, including minimal toxicity, straightforward manufacturing, and excellent biocompatibility made possible by the presence of biocompatible and biodegradable