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Chapter 4
Biological Smart Materials: Materials forCancer Treatment
DebasishPanda, MansiAgarwal, BeautyKumari, PrabhuduttaHota, andAjayAgarwal
Abstract The eld of biomedical materials has witnessed signicant advance-
ments in recent years, leading to the development of novel smart materials capable of interacting intelligently with the biological environment. This book chapter com­prehensively explores the synthesis, applications, and safety considerations of nanomaterials in the context of cancer treatment. The chapter begins with an intro­duction to nanotechnology and its signicance in biomedical research and cancer therapeutics. Next, the chapter explores the synthesis of nanomaterials, covering both top-down and bottom-up approaches. The top-down approach involves the fab­rication of nanoparticles (NPs) from more extensive materials through techniques such as milling and lithography. In contrast, the bottom-up approach focuses on assembling nanoscale building blocks to form NPs using chemical synthesis and self-assembly methods. It highlights the importance of material selection, process­ing techniques, and integrating functional components, such as NPs, nanobers, and hydrogels, to enhance their performance and efcacy. Furthermore, the chapter dis­cusses bioconjugation strategies for biomedical applications, emphasizing their role in improving NP functionality and targeting abilities for cancer treatment. Various
D. Panda RIMS Group, Indian Institute of Technology (I.I.T.), Jodhpur, India
Department of Electrical Engineering, Indian Institute of Technology (I.I.T.), Jodhpur, India
Department of Biomedical Engineering, All Indian Institute of Medical Science (AIIMS), Jodhpur, India
M. Agarwal · B. Kumari Department of Bioscience and Bioengineering, Indian Institute of Technology (I.I.T), Jodhpur, India
P. Hota Department of Biotechnology, National Institute of Technology (N.I.T), Rourkela, India
A. Agarwal (*) RIMS Group, Indian Institute of Technology (I.I.T.), Jodhpur, India
Department of Electrical Engineering, Indian Institute of Technology (I.I.T.), Jodhpur, India e-mail: ajayagarwal@iitj.ac.in
A. Kumar etal. (eds.), Applications of Biotribology in Biomedical Systems,
https://doi.org/10.1007/978-3-031-58327-8_4
113© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
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techniques, including surface modication and functionalization, are discussed to enhance the biocompatibility and specicity of NPs in targeting cancer cells. The chapter further delves into specic types of NPs used in cancer treatment. Plasmonic NPs, known for their unique optical properties, are examined for their applications in cancer therapy. Their use in photothermal therapy (PTT) is discussed, highlight­ing their potential in targeted cancer cell destruction. Inorganic-based NPs, speci­cally those employed in drug delivery systems and PTT, are investigated for their effectiveness in cancer treatment. Their controlled drug release mechanisms and targeted therapy capabilities are explored, showcasing their potential in combating cancer cells. Upconverting NPs, which can convert low-energy photons into high­energy emissions, are discussed in the context of cancer treatment. Their applica­tions in PTT are explored, highlighting their potential for precise cancer cell targeting and destruction. Inspired by nature’s mechanisms, biomimetic-based materials for cancer treatment are examined. These materials mimic biological sys­tems to enhance PTT, offering promising avenues for targeted cancer therapy.
Keywords Nanomaterials · Photothermal therapy · Photodynamic therapy · Targeted cancer therapy

4.1 Introduction

In the realm of modern science and healthcare, an awe-inspiring transformation is taking place at the intersection of nanotechnology and biomedical research. At the forefront of this revolution are biological smart materials, particularly nanomateri­als, which are poised to redene the landscape of cancer therapeutics [1]. These minute structures exhibit extraordinary properties that enable precise interactions at the cellular and molecular levels, propelling them into the spotlight for innovative approaches to combat diseases, especially cancer. These materials have the potential to revolutionize medication delivery, diagnosis, and therapy by navigating the com­plex pathways of the human body, ushering in a new age of customized medicine [2]. To avoid toxicity, lack of selectivity, and improve drug capacity and bioavail­ability, nanomaterials have been created for a broad range of cancer treatments that target cancer cells, the tumor microenvironment (TME), and the immune system [3]. Cancer, an enigmatic and fatal disease continues to be investigated by medical research, necessitating innovative and precise therapy tactics to enhance patient out­comes [4]. In order to avoid toxicity, lack of selectivity, and improve drug capacity as well as bioavailability, a variety of cancer medicines have been created using nanomaterials that target cancer cells, TME, and immune system [5]. Top-down and bottom-up synthesis methods are the two basic strategies for creating nanomaterials. The top-down method reduces the structure’s size to a nanoscale level, whereas the bottom-up approach builds a massive nanostructure from smaller atoms and mole­cules [6]. Understanding these synthesis methods is vital for unlocking the future potential of nanomaterials for cancer therapy and tailoring their characteristics to
4 Biological Smart Materials: Materials forCancer Treatment
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specic applications. Bioconjugate methods are created with at least one biologi­cally derived molecule in order to provide targeted drug delivery, reduce off-target effects, and improve therapeutic effectiveness [7]. These bioconjugates are cutting­edge treatment modalities with potential synergistic anticancer effects, and they have the strength to outperform the drawbacks of chemotherapeutics. To get around these problems, researchers have combined different molecules, transport mecha­nisms, and imaging modalities with therapeutic agents or medications [8].
Plasmonic NPs and their assemblies have been widely used in biosensing, opti­cal imaging, and biomedicine over the last few decades, and are one of the most stimulating applications of nanomaterials in cancer therapy by selectively targeting cancer cells through heat or light-induced effects [9]. The physicochemical features of high-Z plasmonic NPs provide them with the ability to sensitize radiotherapy. Plasmonic NPs allow light to be coupled to nanoscale objects through the collective motion of conduction of plasmons in metals [10]. Due to their capacity to increase therapeutic effectiveness by focusing on ligands while minimizing off-target adverse effects via drug adsorption and penetration, inorganic-based NPs like metal oxides and quantum dots offer various potential benets for drug delivery in the treatment of cancer [11]. These NPs have developed the ability for integrated therapeutic capabilities, such as anticancer effects through cytotoxicity, repression of onco­genes, and blockage of cancer cell signaling pathways [12]. For a variety of biologi­cal applications, including illness detection, medication administration, bioimaging, and cancer treatment, organic-based NPs with specic characteristics have drawn considerable interest [13]. Particularly, organic NPs have shown excellent promise in drug delivery, bioimaging, and phototherapy. These NPs have distinguishing qualities including tailorable synthesis, fast processing, optimal biocompatibility, and minimal cytotoxicity [14]. Biomolecules such as nucleic acids, peptides, or proteins have also been extensively exploited in the construction of useful nano­structures with a variety of topologies and dimensions, including medicines, uo­rescent dyes, and π-conjugated semiconducting polymers [15]. Furthermore, upconverting NPs (UCNPs), with their potential to convert near-infrared light to higher energy emissions, are efcient approaches in deep tissue imaging and ther­apy. In response to near-infrared (NIR) light stimulation, UCNPs are capable of generating high-energy visible light that activates nearby photosensitizer (PS) mol­ecules to produce singlet oxygen and destroy cancer cells [16]. The advancement of nanotechnology allows for the integration of different types of biomaterials onto the surface of NPs. Drawing inspiration from nature, biomimetic-based materials pro­vide highly targeted and effective treatment options through drug delivery, photody­namic theory (PDT), and photothermal theory (PPT) approaches [17]. This mimicry strategy promotes the escape of biomimetic NPs from immune system clearance and decreases the possibility of potential toxic side effects [18]. As we expand fur­ther in the eld of nanomaterials for cancer therapy, it is essential to address poten­tial concerns, such as toxicity and immunogenicity [19]. Particle size, shape, surface area, and surface chemistry of NPs determine their toxicity, which is caused by their predominate accumulation in organs with strong phagocytic activity, primarily in the liver, kidney, and spleen. NPs may be delivered through inhalation, ingestion, or
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skin penetration [20]. At the respiratory, cardiac, reproductive, renal, cutaneous, and cellular levels, toxic effects have been seen that might be hazardous to the environ­ment, animals, and human health, Therefore, the assessment of the safety proles of these novel materials is crucial for their effective translation into clinical applica­tions, assuring patient safety and optimal therapeutic outcomes [21]. From nanoscale material manipulation to strategic bioconjugation methods, these novel methodolo­gies hold the possibility of changing precision medicine. A harmonious conver­gence of scientic innovation and therapeutic potential is orchestrated by the symphony of plasmonic NPs, inorganic and organic-based NPs, and biomimetic materials. With each new discovery, we get closer to a future in which nanomateri­als, pushed by interdisciplinary collaboration, catapult us beyond the boundaries of conventional medical treatments. The use of nanomaterials for delivering immune preparations results in a more powerful and long-lasting immune response than a single immune preparation [22].
D. Panda etal.
4.2 Surface Modication toIncrease theBiocompatibility
Surface modication of 2D materials is a promising approach to enhance their bio­compatibility for theranostic applications. By modifying the surface properties, such as charge, hydrophobicity, and functional groups, it is possible to improve the interaction between 2D materials and biological systems, minimize cytotoxicity, and enable their use in various biomedical applications [23]. Here are some com­mon surface modication strategies for increasing biocompatibility.

4.2.1 Surface Functionalization

Surface functionalization modies the surface characteristics of 2D materials by adding functional groups or molecules to their surface [24]. To do this, a number of chemical processes may be utilized, including silanization, thiolation, and diazo­nium chemistry. In the case of silanization, for instance, a silane compound reacts with the material’s surface to create covalent connections between the molecules of the silane and the atoms on the surface [25]. The addition of biocompatible poly­mers, such as polyethylene glycol (PEG), can create a hydrophilic and stealth-like surface, reducing protein adsorption and immune response. This introduces new functional groups and changes the surface properties of the 2D material. Functional groups like amino (-NH2) or carboxyl (-COOH) can be introduced, which can serve as reactive sites for further bioconjugation or facilitate interactions with biological molecules [26]. These functional groups can also impart hydrophilicity or hydropho­bicity to the surface, depending on the specic modication. By controlling the type
4 Biological Smart Materials: Materials forCancer Treatment
and density of the functional groups, the surface properties can be precisely tailored to enhance biocompatibility and enable specic interactions with biological systems.
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4.2.2 Bioconjugation

The process of bioconjugation involves the covalent bonding of bioactive mole­cules, such as antibodies or aptamers, to the surface of 2D materials [27]. This strategy enables specic targeting and recognition of cells or biomolecules, enhanc­ing biocompatibility and enabling targeted theranostic applications. Bioconjugation can be achieved through various methods, including surface functionalization with reactive groups or linker molecules. The bioactive molecules can be covalently attached to the modied surface, providing specic binding sites for targeted inter­actions [28]. Examples include conjugating antibodies to the surface of 2D materi­als to enable targeted binding to cancer cells or disease indicators. This focused binding may improve the effectiveness and reduce side effects of selective diagnos­tics or the administration of therapeutic medicines to certain cells or tissues [29].

4.3 Synthesis Approach

The fabrication techniques for 2D materials encompass processes utilized to create materials featuring two-dimensional structures, like graphene, transition metal dichalcogenides (TMDs), and layered substances. These methods are pivotal in yielding top-tier 2D materials with regulated attributes and architectures [30]. Numerous synthesis strategies have been formulated, encompassing the hydrother­mal approach, Chemical Vapor Deposition, and Wet Chemical Method. Let’s delve into these methods in greater detail.

4.3.1 Hydrothermal Method

The hydrothermal method stands as a prominently employed synthesis technique in crafting 2D materials. This process entails the reaction of precursor solutions or suspensions within an aqueous environment characterized by high pressure and temperature [31]. The reaction occurs within an autoclave or reaction vessel engi­neered to endure the requisite high-pressure conditions. Undoubtedly versatile and extensively utilized, the hydrothermal method facilitates the creation of top-tier materials endowed with controlled attributes [32]. This renders it well-suited for diverse applications spanning electronics, energy storage, catalysis, and the bio­medical realm.
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4.3.2 Chemical Vapor Deposition (CVD)

CVD is a widely used method for the synthesis and growth of thin lms and 2D materials. It involves the building up of a thin lm material onto a substrate by intro­ducing reactive gases into a reaction chamber. Within this chamber, the gases undergo reactions, resulting in the deposition of the desired material onto the sub­strate’s surface [33]. In the CVD process, precursor gases containing the targeted elements are introduced into the reaction chamber, typically maintained at elevated temperatures. These precursor gases can be in the form of vapors, liquids, or solids that vaporize during the process. Inside the chamber, the precursor gases undergo chemical reactions, leading to the formation of volatile by-products and the deposi­tion of the desired material onto the substrate [34].

4.3.3 Wet Chemical Method

It is also known as wet synthesis or solution-based synthesis, which involves the chemical reaction of precursors in a liquid solvent to form the desired material. It is a versatile and widely used method for the synthesis of various nanomaterials. In this method, the precursors are dissolved in a solvent to form a reaction mixture. The choice of solvent depends on the nature of the precursors and the desired properties of the nal product. The reaction mixture then encounters specic conditions—such as temperature, pH, and stirring—to initiate and regulate the chemical processes [35]. The chemical reactions in the wet chemical method can include precipitation, hydrothermal reactions, sol-gel processes, or reduction reactions, among others. These reactions result in the formation of nanocrystals, NPs, or other nanomaterials. Wet chemical synthesis has benets over dry chemical synthesis, including ease of synthesis, scalability, and control over the size, shape, and content of the produced materials. It makes it possible to create a variety of nanomaterials, such as metal nanoparticles (NPs), quantum dots, metal oxides, and nanocomposites [36].

4.4 Plasmonic Black Bodies (PBBs)

The realm of modern healthcare is witnessing a transformative innovation known as PBBs, a remarkable class of materials and structures characterized by their unique ability to exhibit enhanced absorption and emission of light due to plasmonic effects. As a pioneering eld within nanophotonics, PBBs have emerged as a prom­ising frontier in addressing crucial challenges in cancer treatment, drug delivery, imaging, and beyond [37]. Harnessing the intriguing behaviors of surface plasmons, PBBs hold the potential to revolutionize the landscape of precision medicine by offering tailored and efcient solutions to longstanding limitations in existing
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therapies [38]. This not only uncovers the multi-faceted importance of PBBs in today’s biomedical research but also unveils the varied spectrum of PBB types. Within this array, standout examples include gold NPs [39] acclaimed for their robust plasmonic behavior, making them indispensable in drug delivery and ther­anostics. Silver NPs, sharing similar plasmonic properties, nd application in drug delivery and antibacterial contexts [40]. Gold or silver core-shell NPs are examples of core- shell structures, couple metallic cores with protective dielectric shells, ensuring enhanced stability, biocompatibility, and controlled therapeutic release. Equally compelling, hybrid structures like mesoporous silica-coated PBBs harness the power of gold or silver NPs encased within a mesoporous silica layer, enabling efcient drug loading, controlled release, and plasmonic characteristics suitable for therapy and imaging [41]. Polymer-encapsulated PBBs, exemplied by polymer­coated gold nanorods, amalgamate plasmonic behavior with biocompatible poly­mers, ensuring stability, prolonged circulation, and controlled release [42]. Similarly, plasmonic nanostructures like plasmonic nanoshells, with hollow structures com­posed of dielectric cores and metallic shells, and plasmonic nanocages, exhibiting porous walls and large surface areas, stand as remarkable entities with potential in targeted drug delivery and imaging [43]. This diverse spectrum of PBBs holds pro­found implications for elevating precision medicine through rened treatment approaches and augmented therapeutic outcomes. This introductory glimpse not only highlights the remarkable potential of PBBs in reshaping the landscape of modern healthcare but also paves the way for a profound journey into their intrica­cies and vast potential. As we delve further, we will uncover how these unique materials stand at the intersection of innovation and biomedical research, poised to propel us beyond the boundaries of conventional therapies and into a new era of precision medicine.

4.4.1 Gold NP (AuNPs)-Based PBB

In the dynamic landscape of modern biomedical exploration, the integration of AuNPs has surfaced as an avenue of remarkable promise and transformative poten­tial. These NPs, renowned for their extraordinary plasmonic attributes, especially within the visible and near-infrared realms, are poised to reshape the landscape of drug delivery and theranostics. Utilizing these characteristics, localized surface plasmon resonance (LSPR) enables Au NPs to effectively absorb and scatter light across a wide range of wavelengths. They are adaptable for a variety of biological applications, including drug administration and theranostics, because of their tun­ability, which permits modication of their absorption and scattering characteristics [44]. In drug delivery, Au NPs serve as carriers for therapeutic agents, providing several benets. Their small size allows for easy penetration into tissues, while their large surface area enables high drug-loading capacities [45]. Additionally, the sur­face of Au NPs may be functionalized with targeting ligands like antibodies or peptides to make it easier for target cells or biomarkers to be recognized and bound.
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By enhancing the accumulation of therapeutic chemicals in the intended areas, this tailored administration improves treatment effectiveness while reducing adverse effects on healthy tissues [46]. Au NPs also play a crucial role in theranostics by combining therapeutic and diagnostic functions. Their unique plasmonic properties enable enhanced imaging capabilities. In techniques like dark-eld microscopy and photoacoustic imaging, Au NPs act as contrast agents, enhancing contrast and reso­lution for precise imaging. This imaging aspect allows for real-time monitoring of drug delivery, assessment of treatment response, and visualization of therapeutic efcacy. Furthermore, Au NPs can be utilized in hyperthermia-based therapies [47]. By harnessing the plasmonic properties of Au NPs, localized heating can be achieved when exposed to light, such as NIR laser irradiation. This localized hyper­thermia effect selectively damages cancer cells while sparing healthy tissues, offer­ing a promising approach for targeted cancer treatment. The combination of targeted drug delivery and hyperthermia-based therapies using Au NPs holds great potential in improving treatment outcomes and minimizing adverse effects [48]. Moreover, the stability and biocompatibility of Au NPs, along with their tunability through size and surface modications, make them well-suited for biomedical applications. As we delve into their distinctive capabilities, AuNPs unveil a pathway toward pre­cision medicine, presenting a sophisticated framework for rened therapeutic strat­egies and amplied diagnostic methodologies. These NPs can be engineered to have optimal properties for drug delivery, such as controlled release proles and long circulation times in the body [49]. Researchers, such as Choi etal. and Li etal., have explored the synthesis of Au-based nanostructures like Au@PDA nano worms and GNR@PDA.Choi etal. [50] employed dopamine to synthesize gold nano­worms (AuNWs) encapsulated within a polydopamine (PDA) shell. The process involved the rapid assembly of citrate-capped gold NPs into nanoworm structures within a minute. Subsequently, dopamine initiated self-polymerization over 60min, facilitating the growth of a conformal PDA shell on the outer surface of the AuNWs. This PDA shell signicantly enhances the stability of the internal gold nanoworm structure, resulting in core-shell Au@PDA nanoworms, with each worm possessing around 4–5 gold cores. This synthesis approach not only ensured stability but also precise control over the structure of the resulting Au@PDA nanoworms, rendering them amenable to a range of applications. In another study by Li etal. [51], they concentrated on creating GNR@PDA NPs, in which gold nanorods (GNRs) were created via a seed-mediated technique and then covered with a shell made of poly­dopamine. Figure4.1a shows the form and size of as-prepared GNRs as determined by TEM.High-quality GNRs had an aspect ratio of 3.6 (average width: 22nm; average length: 81nm). The procedure for generating PEGylated gold nanorods (GNRs) encompassed mixing GNRs with mPEGSH followed by their collection through centrifugation. The PEGylated GNRs were subsequently suspended in a Tris buffer and subjected to sonication prior to the addition of dopamine. Dopamineis self- polymerized and coated onto the surface of the PEGylated GNRs. The resulting GNR@PDA NPs were collected through centrifugation. Figure4.1b, c represents the TEM images of GNR@PDA NPs. The polydopamine shell contributed
4 Biological Smart Materials: Materials forCancer Treatment
Fig. 4.1 Synthesis of gold nanorods. (a) Aspect ratio of high-quality GNRs. (b, c) TEM images of GNR@PDA NPs. (d) LSPR peak of CTAB-capped GNRs. (e) Absorption spectra of GNRs@PDA PEGDOX.Photothermal stability test invivo. (f) Photothermal stability of GNRs. (g) Connection between pH and laser irradiation. (h) Tumor ablation with laser irradiation. (i) Comparison of the tumor weight with the control group. (j) PA imaging of the GNRs nanocarrier invivo grouping of the xenograft-bearing mice. (l, m) Photothermal conversion efciencies of GNR nanocomposites at two different concentrations. (Reprinted (adapted) with permission from American chemical society [52])
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additional functionalities and stability to the gold nanorods, enhancing their proper­ties for various applications. Figure4.1d shows the LSPR peak of CTAB-capped GNRs at 850 nm.

4.4.2 Silver NPs (Ag NPs)-Based PBB

Due to their LSPR effect, the Ag NPs have remarkable plasmonic properties that are especially noticeable in the visible range. These Ag NPs have the capacity to ef­ciently capture and manipulate light, rendering them a compelling candidate for PBB applications. In the realm of drug delivery and theranostics, Ag NPs offer a myriad of advantages [53]. Functioning as versatile carriers, their small size and substantial surface-to-volume ratio enable efcient drug loading. Moreover, Ag NPs’ plasmonic attributes can be harnessed to achieve controlled drug release at specic sites via external stimuli like light or temperature [54]. Under light irradia­tion, Ag PBBs generate localized heating, facilitating on-demand drug delivery. Augmenting their potential, the incorporation of targeting ligands enhances binding to cancer cells, ensuring precise drug delivery. Ag PBBs also excel in theranostics by integrating therapeutic and diagnostic roles. Their plasmonic properties enhance
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imaging capabilities, making them indispensable contrast agents for optical imag­ing techniques. Capitalizing on Ag NPs’ scattering and absorption properties bol­sters image resolution, allowing real-time observation of drug delivery and treatment efcacy. To address oxidation concerns, surface functionalization and size, shape, and aggregation control strategies are employed, safeguarding their stability. By coating Ag NPs with biocompatible materials, their circulation longevity is improved, fostering enhanced therapeutic outcomes. Altogether, the remarkable plasmonic features of Ag NPs open new vistas for precise drug delivery and ther­anostic endeavors, holding the potential to transform biomedical applications [55]. Researchers, such as Mondal etal. and Bose etal., have employed various synthesis methods to create tailored Ag NPs for specic applications. These include the cre­ation of plasmonic silver triangular nanoprisms coated with polyvinyl alcohol for enhanced physicochemical qualities and the manufacture of anisotropic silver NPs with surface alterations for targeted drug administration. Mondal et al. [56] employed a synthesis method to create plasmonic anisotropic silver NPs (AgNPs). The process involved mixing AgNO3 and citrate solutions, the addition of hydrazine hydrate immediately after that careful pH control was maintained throughout the synthesis. Subsequently, folic acid was conjugated to the AgNPs, resulting in folate receptor-targeted AgNPs (FA-AgNPs). Further modication involved quenching quercetin (QRC) onto the surface of the FA-AgNPs, leading to the formation of QRC-FA-AgNPs. In a study by Bose etal. [57], dynamic chemical synthesis of polyvinyl alcohol-coated plasmonic silver triangular nanoprisms (PVA-SNT)was accomplished. The synthesis process involved mixing a polyvinyl alcohol aqueous solution with AgNO3 and sodium citrate, followed by the addition of H2O2 and NaBH4. Color changes in the resulting solution indicated the successful formation of PVA-coated silver triangular nanoprisms. A similar synthesis procedure was employed to synthesize silver triangular NPs (SNT), replacing the PVA solution with deionized water. The synthesized PVA-SNT and SNT NPs underwent charac­terization using various techniques.

4.4.3 Platinum NPs (Pt NPs)-Based PBB

Pt NPs also exhibit plasmonic behavior in the UV-visible range, which presents potential value in drug delivery and theranostics applications. Although Pt NPs are less commonly explored in this context compared to other metals like gold (Au) and silver (Ag), they offer unique advantages. In the eld of drug delivery, Pt PBBs serve as carriers for therapeutic agents. Their small size and large surface area-to­volume ratio enable efcient drug loading, allowing for precise control over drug release [58]. Additionally, the plasmonic properties of Pt NPs can be utilized to trigger drug release through light irradiation, providing a means for targeted and controlled drug delivery. By utilizing external stimuli such as light, localized heat­ing can be generated, facilitating the release of drugs specically at the desired sites. Surface functionalization of Pt NPs with targeting ligands enhances their specicity
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