Abstract

Nanotechnology is the most common and frequently used technology that aims to improve the efficacy of medical procedures, sometimes known as Nanomedicine. With their impressive pharmacological efficacy as nanomedicines and delivery systems, nano materials have been recognized as attractive diagnostic and chemotherapeutic tools to treat diseases. To treat a wide range of solid malignant tumors, Drugs built on platinum complexes are now the foundation for many other therapies.  They are often used to treat a variety of solid tumors in the clinic, including head and neck, colorectal, lung and other malignancies. Cell-specific targeting with nano-carriers is possible using both active and passive techniques. This paper provides a thorough overview of platinum-based drug delivery system with the help of nanotechnology. Their mechanisms of action used in the treatment of cancer and potential for further development are all anticipated.

Key Words

Nanomedicines, Platinum Drugs, Chemotherapeutic, Pharmacological drugs

Introduction

With over 23% of all death reports, cancer is thought to be the second most common cause of death (Hosseini et al., 2016). Since cancer treatment has proved difficult many different therapeutic approaches have been investigated (Shinde et al., 2022). Currently surgery, radiation and chemotherapy are the most effective therapeutic techniques. Cytotoxic chemical or biological substances are used in chemotherapy to kill cancer cells. A recent phrase created from the words therapies and diagnostics is theranostics. A new field of personalized medicine called theranostics combines a therapeutic and diagnostic agent in a single formulation, which is guided by a ligand that targets cells that are malfunctioning (Peng et al., 2015; lyer et al., 2013; jain et al., 2013). For cancer theranostics, numerous strategies, including those that use nanomaterials, metal complexes, and small molecules, have been developed. Additionally, nanoparticles can be directly mixed with medicinal and diagnostic substances. Even though clinical usage of nanomaterials as transport vehicles has been permitted for a long time, the full translation of the nanomaterial-based theranostic system from bench to bedside has faced major hurdles (Zhang et al., 2023). Metal, lipid, and polymer nanoparticles (NPs) exhibit a variety of biological characteristics that can be used for theranostic purposes.

 

Nanotechnology as a Drug Delivery System

Nanotechnology based drug delivery systems (NTDDS) can be seen as a viable means of enhancing patient compliance and increasing treatment results (Sahu et al., 2021). Nano science, which combines with traditional disciplines like applied health, molecular chemistry, molecular science, pharmaceutical science, optics and even engineering is the sole way to learn about the unique features of matter. The most prevalent and financially successful technology of these decades has arisen, and research has proved that it is crucial for maintaining human existence (Galluzzi et al., 2012).

Platinum anticancer drugs have been used for decades to treat a variety of cancers, including the bladder, cervical, colorectal, head, pulmonary, and throat cancers, as well as ovarian and testicular cancer (Wani et al., 2017; Zhang et al., 2023). Chemosynthetic platinum-based antitumor medicines have been successfully researched and used to treat a variety of cancers (Xiao et al., 2018; imran et al., 2018].

With a focus on its usage for drug administration via Platinum complexes, we examine the use of nanotechnology for medicinal purposes in this review. A technique that has promise for the development of intelligent therapeutic systems is the use of smart medication delivery systems. In this study, we first provide an overview of the most widely used platinum medications, including platinum (IV), platinum (II), and non-classical platinum (II) medications that have all received clinical approval. The overview of platinum complex-based nano-carrier based drug delivery systems (NDDSs) is then provided (Anarjan, 2019).

 

The Benefits of Using Nanoparticles for Drug Delivery

§ The ability of nanotechnology to be absorbed into the body without causing any adverse effects or chemical reactions is crucial when using it as a medicine delivery method.

§ Drug degradation and regulated delivery aspects can be synchronized fast.

§ Due to the improved biological availability of the drug at a specific location for a sustained length of time and the exceptionally minimal drug wastage, it is the optimal method for drug administration.

§ Additionally, it can increase a drug's half-life in the bloodstream and the ability of weakly water-soluble medicines to dissolve.

§ The effectiveness of nanotechnology is such that it can increase the activity and dispersion of pharmaceuticals in comparison to conventional drugs and also ensure patient consent and satisfaction. Nanotechnology is far more affordable than other types of traditional medications (Wani et al., 2022)




 

Table 1

Brief description of Nanosystems, including features and purposes (Koo et al., 2005)

Types of Nano             particles	Characteristics	Functions
1. Liposomes	Made up of a hollow main part and a liquid bilayer.	a common method for delivering drugs to treat cancers
2. Polymeric	A polymer that immune cells can absorb, such as PCA or PLGA, is employed.	Effective at delivering drugs because they are hydrophobic.
3. Nanotubes	Insoluble in Water	Used for low-dose targeting of certain cancer cells.
4. Nanocrystals	Establish very stable nano-suspensions.	Mainly used for HIV based drug delivery.
5. Dendrimers	On the outside, there are working end groups, layers of branched, repetitive units, and a core. multivalency levels.	It is effective for both phyllic and hydrophobic medicines. used as a coating agent for medications to protect them
6. Solid Lipid Nano-particles	composed of layers that are solid, like tripalmite	effective drug administration methods, including pulmonary, rectal, oral, and ophthalmic.
7. Polymeric micelles	Composed of amphiphillic surfactants.	Drug delivery to tumour cells that is efficient and has fewer negative effects
8. Nano-capsule	Spherical structures with a dielectric core.	Cancer treatment. Biomedical imaging.
9. Ceramic Nanoparticles	Constructed from inorganic materials having porous properties, such as alumina.	Hazardous, non-biodegradable shabby drug loads.
10. Gold Particle	composed of vesicles i.e hydrophobic and hydrophilic molecules that are plated in gold.	being biocompatible. sustainable and reliable.

Mechanism of Targeted Nanoparticles

There are two ways that nanoparticles connect to the drug surfaces and deliver the medication to the body's sick tissue (Sahu et al., 2021).



Passive Targeting:

Enhanced Permeability and Retention Effect.

While the enhanced permeability and retention (EPR) effect, which favors the accumulation of therapeutic drugs in the interstitial space of tumors as a result of the deterioration of the vascular and lymphatic system effect, is a result of passive targeting (Pelicano et al., 2006)

Nanoparticles need to be able to circulate in the bloodstream for longer periods of time and have a better chance of getting to the targeted tumor areas. Nanoparticles can gather in tumor tissues due to the special traits of tumor cells. Cancer cells that are dividing quickly require new blood arteries to feed them with nutrition and oxygen. Due to this, the tumor arteries become dilated and have a large number of pores that display gap junctions between lymphatic and endothelial tissues (Lata et al., 2017;Cho et al., 2008).

Figure 1

Passive Targeting by Nanoparticles



Micro-environment of Tumor vessels

Another component of passive targeting is the specific environment that surrounds tumor cells, which is distinct from that of healthy cells. The vascular bed and stroma, functional lymphatic and interstitial pressure, and their capacity to maintain homeostasis are a few of the fundamental elements impacting the tumor microenvironment under mechanical stress (Allen & Lim, 2022). Because of a deficiency in oxygen and nutrients, rapid-growing tumor cells have a high metabolic rate that they are typically unable to maintain. In order to gain additional energy, tumor cells use glycolysis, which creates an acidic environment (Li & Burgess, 2020;Shinde et al., 2022).




Active Targeting by Nanoparticles

The specificity of passive targeting techniques has inherent limitations. The incorporation of a targeted ligand in polymer-drug conjugates can get beyond these restrictions (Lata et al., 2017). The recent development of a wide array of liposomes, polymers, nanotubes, and metals as drug delivery carriers has boosted the number of drugs that can be coupled to targeted nanoparticles without compromising their targeting affinity. By using both passive and active targeting strategies, nanoparticles can boost the intracellular concentration of drugs in cancer cells while limiting harm to normal cells (Cho et al., 2008).




Expression of an Antigen or Receptor

Numerous characteristics of cell-surface antigens and receptors would make them particularly attractive tumor-specific targets (Allen, 2002). Prior to that only tumor cells should display them, not healthy cells. Secondly, they must be expressed consistently across the targeted tumor cells. Finally, it's critical to prevent the circulation from becoming contaminated with cell surface antigens and receptors.




Internalization of Targeted Conjugates

Receptor-mediated endocytosis typically causes internalization. Fig. 2. Using the folate receptor as an example, the encircling plasma membrane creates an endosome by encroaching over the combination of the receptor and ligand when a chemical that targets folate interacts to the cell's surface folate receptor. Target organelles get newly produced endosomes. When the pH level inside the endosome rises to an acidic level and the medication is liberated from the conjugate and enters the cytoplasm once the lysozymes are activated, if it possesses the physicochemical properties needed to penetrate the endosomal membrane. Depending on the medication, the target organelle then traffics the released medicines. The cell membrane receives the folate receptor that was released during conjugation and interacts with new conjugates that are folate-targeted while waiting for the second cycle of transport to start (Leamon & Reddy, 2004).

Figure 2

Active Targeting by Nanoparticles



Platinum Drugs

Carboplatin, cisplatin, and oxaliplatin are the three primary platinum anticancer medications with clinical applications. Platinum-based medications should, ideally, solely kill tumor cells while sparing healthy cells any harm. However, platinum medicines have very low selectivity, in addition to killing malignant cells, they also harm normal cells. Platinum medicines have suffered from severe side effects, systemic toxicity, and acquired and intrinsic resistance, which have reduced their therapeutic efficacy. Because of cisplatin's high level of effectiveness, the research and development of platinum medications has rapidly increased, and thousands of them have undergone clinical testing. It is feasible to distinguish between synthetic platinum medicines of the Pt (II) and Pt (IV) kinds based on the valence of platinum atoms at either +2 or +4 (Zhang et al., 2022)




Classical Pt (II) Drugs

The first Pt (II) medication found was cisplatin (Gosh et al., 2019). Since Rosenberg and colleagues unintentionally made the finding in 1965 while looking into how electric fields effect E. coli differentiation, cisplatin has been shown to have anti-cancer activity (Arnesano & Natile, 2009). Cisplatin, a medication with a broad-spectrum anti-cancer activity, has been used to treat a variety of cancers, including ovarian cancer, testicular cancer, lung cancer, cancer of the bladder, cancer of the cervix, tumors of the head and neck, etc. Its usage in clinical settings was severely constrained due to its significant systemic adverse responses and unfavorable consequences, which included renal toxicity, gastrointestinal reaction, neurotoxicity, ototoxicity (Graham et al., 2004).

The second-generation platinum drug carboplatin gained widespread acceptance in 1989 and was afterwards used mostly to treat head and neck cancer, ovarian cancer, and non-small cell lung cancer (NSCLC).

The second-generation platinum medication nedaplatin, which was first marketed under the trade name 254-S, was only permitted to be sold in Japan. This platinum medication has non-leaving cis ammine ligands, just like cisplatin and carboplatin. Nedaplatin is primarily used to treat breast cancer, NSCLC, SCLC, esophageal cancer, and head and neck cancer in clinical settings. Nedaplatin usage is rising as a result of clinical trials (Wheate et al., 2010).

Figure 3

Structures of Platinum (II) Complexes



Nedaplatin, a second-generation platinum drug that was initially marketed as 254-S, received authorization in 1995, but only in Japan. This platinum drug, like cisplatin and carboplatin, possesses non-leaving cis ammine ligands. Nedaplatin is mostly used in clinical settings to treat breast cancer, NSCLC, small-cell lung cancer (SCLC), esophageal cancer, and head and neck cancer (Misset et al., 2000). Clinical trials are using nedaplatin more frequently (Peng et al., 2013;Choi et al., 2004).   

Despite the many advantages that cisplatin has over carboplatin, oxaliplatin, and other popular Pt (II) medications, resistance and unpleasant side effects are still a possibility (Garbutcheon et al., 2013; Xu et al., 2022).




Table 2

Clinically approved Pt(II) drugs (Wheate et al., 2010)

Generic name	Research name	Trade name	Cancer type	Side Effects	Area of Acceptance
Cisplatin	CDDP	Platinol	Testicular, Cervical Lymphoma	Nephrotoxicity, Neurotoxicity, Ototoxicity, Nausea	Global
Carboplatin	JM8	Paraplatin	Ovarian, Lung	Myeloablation	Global
Nedaplatin	254-S	Aqupla	Esophageal cancer Breast, SCLC	Peripheral Neuropathy, Ototoxicity	Japan
Heptaplatin	SKI 2053R	SunPla	Gastric Cancer	Nephrotoxicity, Severe nausea and Vomiting, Neurotoxicity	Korea
Oxaliplatin	1-OHP	Eloxatin	Head and neck squamous cell cancers  (HNSCC)	Liver Toxicity Peripheral Neuropathy (Anemia)	Worldwide

 




Non-classical Pt (II) Drugs

Cisplatin offers many advantages over carboplatin, oxaliplatin, and other popular Pt(II) medications, although resistance and unfavourable side effects are still a possibility. Additionally, the low doses of these medications can be administered to the tumour without reaching deadly concentrations due to their limited aqueous stability and high reactivity to bioactive chemicals. To address these problems, numerous structurally distinct non-classical Pt(II) medicines have been developed (Eckardt et al., 2009) 

Figure 4

Non classical Platinum (II) drugs



Table 4

Clinical trials for Pt(II) medications (Eckardt et al., 2009)

Generic Name	Stage	Type of Cancer
Picoplatin	Phase I	Prostate cancer, small cell lung cancer, non-small cell lung cancer, prostate cancer, colon cancer, and lymphoma
BBR 3464	Phase II	SCLC, gastric cancer, and ovarian cancer
56MESS	Phase II	Chemotherapeutic drug superior to cisplatin, anticancer agent.

 




Platinum (IV)

The first orally administered platinum analogue, satraplatin, has a number of potential advantages over other platinum medications, such cisplatin. Its oral bioavailability makes it particularly practical for both patients and healthcare professionals.

Prostate cancer, non-small cell lung cancer, and head and neck cancer are now being treated with satraplatin (JM-216), a Pt (IV) prodrug that does not exhibit cisplatin cross-resistance and can be administered orally (Zhang et al., 2021). Satraplatin has a comparable toxicity profile to that of carboplatin, with no evidence of nephrotoxicity, neurotoxicity, or ototoxicity (Choy et al., 2008).

Figure 5

) Representative Pt (IV) drug structures (b)The JM-216 structure (Zhang et al., 2020)



Figure 6

Mechanics of (a) reduction-sensitive and (b) photo-sensitive Pt (IV) prodrugs (Zhang et al., 2022; Kuang et al., 2020; Li et al., 2022).



Specific Side Effects of Platinum Drugs

9.6 million people worldwide died from cancer in 2018, and there were 18.1 million new cases (Wheate et al., 2010). Numerous advancements have been achieved in conventional cancer therapies like radiotherapy and chemotherapy, which don't seem to be working very well. As some drawbacks, including chemoresistance, prevent it (Um et al., 2019).

Nephrotoxicity, a generic term that covers more than 12 distinct adverse consequences linked to the kidneys' vital filtration, reabsorption, and excretion activities, refers to damage to the kidneys (Bai et al., 2017; Ahn et al., 2002). A patient's hearing and balance are impacted by ototoxicity, or injury to the inner ear. The side effects of drugs containing platinum ear discomfort, tinnitus (echo problem) and vestibular abnormalities. However, the most typical ototoxicity is bilateral irreversible hearing loss (affects balance) (Wheate et al., 2010).

Conclusion and Future Perspective

Nanomedicine is advancing quickly and significantly, which points to its bright future and tremendous potential for creating innovative and effective diagnostic and therapeutic approaches, particularly for cancer. To address the difficulties in cancer therapy, nanomedicine provided a variety of medication delivery alternatives (Oroojalian et al., 2020). There has been a huge increase in the usage of platinum drugs in chemotherapy. One of the most dynamic subspecialties of oncology is the use of drugs with a platinum base. Different cancer types are now being treated using a variety of platinum compounds. The discipline of theranostic NP has seen expanding advancements in disease management. Despite the significant progress that has been made in the field of theranostic NPs, such as active tumor site targeting, many obstacles still stand in the way of its successful application in clinical settings, such as the creation of stimuli-responsive NPs and the viability of therapeutic combinations, the possibility for adopting the controlled-release method and enhancing the therapeutic effects using magnetic fields or photothermal therapy (Biswas et al., 2022). The polymer-based platinum drug delivery technology will undoubtedly drive the medication delivery sector to a better future (Kandasamy & Maity, 2021). The size of the global nanomedicine market is anticipated to increase from an estimated $53 billion in 2009 to more than $100 billion in 2014 at a compound annual growth rate (CAGR) of 13.5%. The potential for creating a system that produces nanoproducts more successfully is limited. Understanding how nanomaterials are dispersed within the body is crucial. In connection with a second restriction, imaging methods are required to monitor the biodistribution of nanomedicine over time (Hosseini et al., 2023). 

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