Carbohydrates based stimulus responsive nanocarriers for cancer-targeted chemotherapy: a review of current practices

ABSTRACT

Introduction

Many nanocarriers have been developed to react physicochemically to exterior stimuli like ultrasonic, light, heat, and magnetic fields, along with various internal stimuli including pH, hypoxia, enzyme, and redox potential. Nanocarriers are capable to respond various stimuli within the cancer cells to enable on-demand drug delivery, activation of bioactive compounds, controlled drug release, and targeting ligands, as well as size, charge, and conformation conversion, enabling sensing and signaling, overcoming multidrug resistance, accurate diagnosis, and precision therapy.

Areas covered

Carbohydrates are ubiquitous biomolecules with a high proclivity for supramolecular network formation. Numerous carbohydrate-based nanomaterials have been used in biological solicitations and stimuli-based responses. Particular emphasis has been placed on the utilization of carbohydrate-based NPs and nanogels in various fields including imaging, drug administration, and tissue engineering. Because the assembly process is irreversible, carbohydrate-based systems are excellent ingredients for the development of stimulus-responsive nanocarriers for cancer-targeted chemotherapy. This review aims to summarise current research on carbohydrate-based nanomaterials, with an emphasis on stimuli-sensitive nanocarriers for cancer-targeted chemotherapy.

Expert opinion

Carbohydrates-based stimulus-responsive nanomaterials have been proved highly efficient for targeted delivery of anticancer drugs, thus leading to effective chemotherapy with minimum off-target effects.

KEYWORDS:

• Carbohydrates
• nanomaterials
• cancer
• stimulus-responsive
• nanocarriers
• chemotherapy

1. Introduction

Cancer is a collective name for a set of diseases defined by the development of aberrant cells (uncontrolled cell division). Malignant tumors are considered the 2^nd leading cause of mortality, after only heart attacks. Cancer is the major cause of death in the world, with approximately 10 million fatalities expected in 2020, accounting for nearly one in every six deaths. Breast, lung, colon, and rectum cancers, as well as prostate cancer, are the most prevalent cancers [1]. Additionally, ten million individuals are diagnosed with cancer each year, totaling twenty million cancer survivors [2]. According to WHO predictions for 2019, cancer is one of the prime or 2^nd crucial reasons for death before the age of seventy years in 112 of 183 nations, moreover, it is the third or fourth major cause of mortality in 23 other countries [3]. For more than three decades, biomedical nanomaterials have been developed and have demonstrated significant effectiveness in tumor control applications such as drug delivery and diagnostics [4]. Most biomass on the earth is made up of carbohydrates, which account for more than 80% of all biopolymers. They are mostly utilized to store energy and for structural reasons. It has been obvious in recent years that carbohydrates regulate a wide array of biological activities. CCIs and CPIs are implicated in cell differentiation, proliferation, inflammation, adhesion, and immunological reactions [5]. Due to the low strength of these interactions, which are often in the micro- to the millimolar range, nature employs many weak interactions to circumvent this constraint (multi valency). Synthetic chemists have imitated nature by using the concept of multi-valency [6]. The CPI and CCI were strengthened by a large number of nanostructures coated with multiple versions of the same carbohydrate ligand [6,7]. Additionally, it has improved water solubility and stability. Numerous research on the utilization of glycosylated scaffolds, including polymers, nanoparticles (NPs), drug delivery systems (DDSs), vaccines, and treatments have been done [6,8,9].

Table 1. Carbohydrate based stimuli-responsive nanocarriers for cancer treatment

Stimuli	nanocarriers	Drug	Cancer	Characteristics	References
pH	drug-conjugated glycopolymer-coated gold NPs	Doxorubicin	Cervical and lung cancer	The NPs selectively released the drug in cancer cells than in healthy cells	[47]
	β-cyclodextrin decorated mesoporous materials	5-fluorouracil	Human glioma U87 MG cells	The NPs exhibited a 60% release at pH 5 and did not release the drug at neutral pH.	[49]
	β-CD-capped DOX-loaded MSN	DOX	HER2-positive breast cancer cells	The NPS exhibited HER2-mediated endocytosis and exerted the significant cytotoxicity toward HER2-positive SKBR3 cells	[50]
	Hydroxypropyl – cyclodextrin based liposomes	paclitaxel	lung adenocarcinoma (A549/T) cell line	They exhibited pH triggered PTX release with improved intracellular accumulation leading to a significant reduction in tumor growth	[51]
	Lithocholic acid and two β-cyclodextrin terminated poly(2-(dimethylamino)ethyl methacrylate) segments	DOX	Breast cancer MCF-7 cells	The carrier exhibited much quicker at pH = 5 than at pH = 7.4 and more efficiently deliver the DOX into the cancer cells due to their different drug release behaviors in the endosome acid condition.	[52]
	Core–shell tecto dendrimers (CSTDs)	DOX	HeLa cells	The nanocarrier provided the frequent release under a slightly acidic pH leads to enhanced intracellular uptake and increased anticancer activity	[53]
Temperature	β-cyclodextrin based multifunctional nanogels	DOX	human epithelial carcinoma cell line, KB cells	Nanogel shrinkage occurs under the influence of temperature switching from 25–42°C and released the encapsulated DOX in KB cells	[71]
	β-cyclodextrin anchored magnetic mesoporous silica nanoparticles	DOX	–	PNIPAM shell collapsed above the lower critical solution temperature and the release of the drug increased	[73]
	graphene oxide (GO) functionalized with carboxymethyl chitosan (CMC), and lactobionic acid (LA)	DOX	liver cancer cell line SMMC-7721	LA-containing composite selectively induces cell death in cancerous cells	[74]
	Pectin-conjugated magnetic GO nanocarrier	paclitaxel	MCF-7 cancer lines	The nanosystem revealed a significant inhibition of MCF-7 cancer cell growth	[75]
	Magnetic hydrogels composed of tragacanth gum poly(acrylic acid) and Fe3O4 nanoparticles	DOX	human epidermoid-like carcinoma (Hela) cells	Fe3O4 NPs induced hyperthermia therapy locally raises the temperature inside the Hela cells at 45 ± 3°C and promotes cell death	[78]
Magnetic	β-cyclodextrin-conjugated superparamagnetic iron oxide	Paclitaxel	HeLa, MCF-7 and CT26 cells	Superparamagnetic iron oxide nanoparticles in the nano-assembly permitted the rapid and efficient targeted drug delivery	[79]
	GA-coated MNP	Rhodamine B	9 L glioma tumors	GA-MNP accumulated 12-fold more in brain tumors than in the healthy brain	[80].
GSH/ Redox	Magnetic iron oxide nanoparticles (MNP) coated with gum arabic (GA)	Chlorambucil	MCF-7 cancer cells	The nanovesicles demonstrated increased selectivity and therapeutic effectiveness when compared to free chlorambucil	[84].
	Glycopolypeptide-based bioactive stimuli-responsive micelles	Rhodamine B	liver cancer cells (HepG2)	Dox-loaded micelles enter into the cancer show a suitable pharmacological effect on the tumor cell	[85]
	Hexadecanol-modified chitosan oligosaccharide polymer micelle coated with hyaluronic acid	Gambogic acid	triple-negative breast cancer	Complex micelle enhanced TNBC tumor cellular uptake and fast drug release due to CD44 receptor-mediated internalization and redox/pH dual-responsive drug release	[87]
	polypeptide nanogel of methoxy poly(ethylene glycol)-poly(L-phenylalanine-co-L-cystine	DOX	4T1 breast cancer treatment	Reduction-responsive polypeptide nanogel simultaneously released the drugs to the tumor cells and synergistically performed antitumor efficacy.	[88]
Enzyme	Supramolecular assembly employing biocompatible sulfato-cyclodextrin	Prodigiosin	MCF-7 and HepG2 cancer cells	drug-loaded NPs kill cancer cells more efficiently via drug release mediated by various enzymes i.e. amylase and hydrolase	[90]
	Nanometric silica mesoporous supports capped with “saccharides	Doxorubicin	HeLa cells	With the addition of galactosidase, DOX release was greatly increased, and effectively internalized by HeLa cells	[92]
	Guar gum-based matrix tablets were loaded with curcumin	Curcumin	Colon cancer	Tablets containing 40% guar gum released 91% of the active ingredient during 24 hours and effectively target the colon cancers	[93]
	Mannose-6-phosphate (M6P) based vesicle	Doxorubicin	HEK-293 cells	M6P lipid assembly underwent morphology change under the influence of enzyme which leads to effective cargo release from the system	[94]
Ultrasound	Ocarboxymethyl chitosan nanodroplets	Doxorubicin	The human prostate cancer cell line PC-3	The viability of PC-3 cells in the O-CS-DOX NDs group was significantly lower than that in the DOX group with ultrasonic irradiation	[99]
	Chitosan-alginate nanoparticles	pAcGFP1-C1 plasmid	HeLa cells and 293 T cells	The prepared nanoparticles protected the DNA from enzymatic digestion and improved the efficiency of gene transfection of HeLa cells and 293 T cells	[100]

Carbohydrates (or saccharides) are one of the four primary groups of macromolecules, along with lipids, proteins, and nucleic acids. Carbohydrates provide unparalleled prospects for nanomedicine applications due to their unique mix of several benefits: (ii) biodegradable/biocompatible (ii) commercially accessible (iv) protein repellent (v) strong water solubility (vii) no agglomeration. Unlike proteins and nucleic acids, the connecting sites between sugar units are not fixed when oligo/polysaccharides are shaped by elongating chains and branch formation. Regioisomers may be produced due to lengthening the sugar sequence at various hydroxy groups, which results in a significant increase in coding capacity. Twenty amino acids yield 6.4 × 10⁷ hexapeptide isomers, but an oligosaccharide with the same number of hexose repeating units yields 1.44 × 10¹⁵ isomers [10]. Additionally, the bulk of carbohydrates are present on the outer membranes of cells, in blood and extracellular fluid [11], providing an optimal biological environment for the intravenous administration of nanomedicines.

Carbohydrate-based nanoparticles are consider as the one of the most dominant macromolecules in nature playing a significant role to treat broad variety of human disease [12,13]. They are naturally occurring polymers that are often portrayed as structural or storage blocks depending on their function and uniformity of monomer. In pharmaceutical science, a long history is present on the use of structural and heteropolysaccharides. They are also reported to be use as immunological modulators, anti-inflammatory drugs and anti-tumor adjuvants in traditional medicine [14]. Diverse polysaccharides have sparked intense interest from scientists for their potential applications in nanotechnology, and successful implementation in designing matrices with control release behaviour, nanogels, films, hydrogels, microspheres, and nanospheres, as well as coating material for other nanostructures, to impart required characteristics such as enhanced stability, safety, low toxicity, hydrophilicity, biocompatibility, and biodegradability [15]. Current efforts have resulted in the development of polysaccharide-based nanomaterials with very effective basic structures for controlled drug release, notably as a vehicle for tumor-targeting, and other biomedical applications [16,17].

Understanding carbohydrate’s characteristics at the molecular level will assist in the clinical translation of ‘sweet’ nanomedicines[18]. Apart from their function in biological signaling, carbohydrates perform a variety of other biological roles, which include energy storage, organelle protection, and amendment in the assets of peptides or proteins [19], all of which could endow the nanomedicine with superfluous innovative characteristics. Additionally, carbohydrates affect the connections and communication between cells and the matrix inside cellular organelles and multicellular organs [20,21]. Exploiting the distinctions between healthy and malignant cells, as well as the information stored in this natural ‘glyco-code,’ may provide a diagnostic and therapeutic tool for cancer [22].

Apart from their biological origins and vital role in biological communication, the inherent hydrophilicity of oligo- and polysaccharides increase their importance for biomedical polymeric research. They are now being studied as biodegradable alternates for PEG to lessen unclear protein adsorption [23]. Similarly to PEG, it has been shown that hydroxyethyl starch (HES) [24–26], a synthetic starch derivative, dextrin [27,28], and other saccharides [21,29] prevent the adsorption of protein on the surface of nanocarriers and lengthen their circulation in the bloodstream. Apart from their biological function of interacting with particular proteins/cell surfaces, carbohydrates serve as an excellent building block for future therapeutics.

Additionally, carbohydrates are biodegradable, which makes them ideal for drug delivery. This not only guarantees that the materials are finally expelled from the body but also serves as a secondary promoter for the release of drugs or their activation by certain enzymes [26,27,30]. For instance, the degree of hydroxyethylation may be precisely controlled to influence the kinetics of HES breakdown. In summary, carbohydrates are interesting materials for fabricating nanocarriers for biomedical applications due to their biological activity, stealth potential, and enzymatic stimulation. The purpose of this article is to summarise current research on carbohydrate-based nanomaterials, with an emphasis on stimuli-sensitive nanocarriers for cancer-targeted chemotherapy. We will explain the formation of these systems and how their attributes are adjusted. There will be a particular focus on the utilization of carbohydrates in biological applications.

2. Stimuli-responsive carbohydrates nanocarrier for cancer-targeted chemotherapy

While chemotherapy is a critical component of treatment for a variety of diseases, anticancer medications are often accompanied by adverse effects, including nephrotoxicity, neurotoxicity, and ototoxicity. Efforts have been undertaken to mitigate adverse effects using biological and pharmacological techniques. Chemotherapy for cancer is a careful mix between response and toxicity; although underdosing impairs efficacy, overdosing leads to severe toxicity. Because cytotoxic action is not restricted to malignant cells but also affects normal cells, non-selective pharmaceutical distribution in the body will always result in significant unfavorable or toxic consequences. Pharmacists responsible for formulation have a substantial challenge in reconciling the two via the development of novel delivery methods for selective distribution [31]. Additionally, since these medicines have a low bioavailability in tumor tissues, greater dosages are necessary, resulting in increased toxicity in normal cells and an increased incidence of multidrug resistance. As a result, it is important to design chemotherapeutics that may target malignant cells passively or aggressively, therefore minimizing unwanted side effects while increasing therapeutic effectiveness.

Nanotechnology may be critical in accomplishing this aim due to its prospective to change cancer diagnosis and therapeutic strategies[32]. Currently, improvements in our understanding of tumor biology and the availability of versatile materials such as polymers [33,34], lipids [35,36], inorganic carriers [37], polymeric hydrogels [38], and biomacromolecular scaffolds [39], have resulted in the development of systems capable of delivering chemotherapeutics to tumor sites with increased therapeutic efficacy. Numerous nanocarriers based on polymers (micelles, polymeric NPs, and dendrimers), lipids (liposomes), organometallic compounds (nanotubes), and inorganic NPs (fullerene, quantum dots, and magnetic NPs) are now introduced for drug delivery [40]. Furthermore, the efficacy of nanoparticles has been further enhanced by using various targeting ligands as the nanoparticles are capable to bind specific receptors and allow the entry of nanoparticles into the cells specifically via receptor-mediated endocytosis [41]. The circulation time of NPS improved after their surface modification which also affects the internalization of NPs in cancer cells. Therefore, the surface of NPs can be modified with some tumor-specific ligands (active targeting) will facilitate the selective internalization of target cells. Additionally. Specific tumor environments offer multiple stimuli to nanocarriers which can be advantageous in designing responsive nanocarriers [42]. These stimuli-responsive nanocarriers are intended to release therapeutic proxies in retort to endogenous and exogenous stimuli i.e. temperature, pH, redox potential, enzymes, and ultrasound [43].

2.1. pH-responsive drug delivery

Due to the pH shift that happens when NPs are endocytosed into a cell, pH-responsive NPs have sparked scientific attention. The pH of the circulation decreases from 7.4 to 6.5 in the early endosomal compartment and to below 5 in the lysosomal compartment. Additionally, there are extracellular locations with a lower pH, such as tumors, which are somewhat acidic (pH 6.4–6.8) [44]. It is not difficult to imagine that particular pH-responsive therapeutic cargos may be engineered to enter individuals and deliver drugs to specific cells or organs in response to pH variations [45,46]. As a result of this modification of carbohydrates, a previous study developed a smart carbohydrate-based pH-responsive DDS for in vivo metabolic research. A pH-responsive drug-conjugated glycopolymer-coated gold NPs was developed by functionalizing them with thiol-terminated glycopolymers and then conjugating them with doxorubicin (DOX) through a pH-sensitive hydrazone linkage. This successful experiment demonstrates that free DOX is more successfully spread in a cancer cell medium with a lower pH than in a healthy cell medium [47]. When mesoporous silica was employed to transport pharmaceuticals (5-fluorouracil (5-FU), doxorubicin (DOX) worked as a ‘gatekeeper’ that regulated the releasing pattern of the drug in correspondence with pH changes [48]. The data of the report declared that the medication absorbed more than 80% of its dosage and was released effectively within 24 hours at a pH of 5 (Figure 1) [49].

Figure 1. The adsorption and release characteristics of 5-FU loaded on pH stimuli-responsive DDSs were investigated. Reproduced with permission from [49].

Another work proposed a pH-responsive, HER2-targeted system with controlled release potential based on a host-guest interaction between HApt-functionalized β-CD and the MSN surface ligated with BM (MSN-BM). This approach was utilized to increase the anti-tumor activity of the cytotoxic drug DOX and the biotherapeutic compound HApt against HER2-positive breast cancer (BC) cells. HApt served as a biotherapeutic and a targeting agent, enabling the administration and absorption of DOX-loaded NPs by HER2-positive cells. At physiological pH (7.4), MSN capping with CD-HApt reduced DOX release and developed stimuli-responsive drug release behavior at acidic pH. MSN-BM/CD-HApt@DOX was rapidly internalized through the HER2 receptor-mediated endocytosis, and DOX and HApt had a synergistic lethal impact on SKBR3 cells overexpressing HER2 [50]. Resistance to many drugs has progressively risen to become the principal hurdle to cancer treatment. To overawed this barrier, hydroxypropyl – cyclodextrin (HP – CD) was used to synthesize liposomes and conduct research on paclitaxel (PTX). Liposomes exhibited strong cytotoxicity and pH sensitivity in vitro studies (A549/T cell lines). Additionally, it has been shown that drug-loaded liposomes inhibit the growth of tumors in vivo [51]. Bai et al. used lithocholic acid as a linker to connect two β-CD molecules (host-guest inclusion interactions) to construct a carrier for doxorubicin. The carrier release rate was found to be much quicker at pH = 5 than at pH = 7.4. The findings might be justified by the fact that the polymer’s side chain stretches contrarily at varied pH settings. Additionally, basic biological studies have shown that the vector’s self-assembly is capable of being absorbed by cancer cells, suggesting that it may have been used in the field of medication delivery [52]. The researchers describe the synthesis of pH-responsive core-shell tecto dendrimers (CSTDs) using benzimidazole (BM) modified generation 3 (G3) poly(amidoamine) (PAMAM) dendrimers (G3.NHAc-BM) as the shell and -cyclodextrin (CD) modified generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers (G5.NHAc-CD) modified. They demostrated thatthe developed system can deliver the packed DOX at a high rate indefinitely and a marginally low pH (pH 6), replicating the acidic tumor microenvironment (TME). Upon comparioson with control pH-insensitive CSTDs, they observed that the drug-loaded pH-responsive CSTDs had a faster intracellular release of DOX with enhanced antitumor efficacy [53].

A calcium carbonate (CaCO₃)-crosslinked hyaluronate (HA) nanoparticle with tumor microenvironment responsiveness was prepared using a ‘green’ technique to successfully transport doxorubicin (DOX) for the treatment of various osteosarcoma stages. When triggered by the acidic tumor microenvironment, the DOX-loaded hyaluronate-calcium carbonate hybrid nanoparticle (HA-DOX/CaCO₃) promptly released DOX at the tumor site. In comparison to free DOX and a non-crosslinked nanoparticle (HA-DOX), HA-DOX/CaCO₃ had the highest inhibitory activity in primary and advanced models of murine osteosarcoma, resulting in efficient tumor inhibition, increased survival time, and decreased side effects [54].

To deliver doxorubicin, B-CD-based pH/Reduction dual-responsive nanocarriers were designed. The constructed nanosystem released more medicine at a pH of 5.0 than at a pH of 7.4, demonstrating that the pH-sensitive triggered drug release performed well. The suggested DDS’s reduction and pH-sensitive properties, as well as its large drug loading capacity, justify its consideration as a viable drug carrier for tumor treatment [55].

Self-targeting hyaluronate (HA) nanogels (CDDPHANG/DOX) are developed to overcome drug resistance by synchronizing the pharmacokinetics, intratumoral distribution, and intracellular release of the topoisomerase II inhibitor doxorubicin (DOX) with the DNAcrosslinking agent cisplatin (CDDP. In drug-resistant MCF-7/ADR breast cancer cells, this HA nanogel displayed pH-responsive release and improved anticancer activity. So the nanogel displayed CD44-positive tumor targeting, MDR-reversing, pH-responsive releasing, and fluorescence/micro-CT dual imaging, as well as synergistic chemotherapeutic actions, indicating good prospects for future clinical drug-resistant breast cancer therapy [56].

A previous study created an acid- and light-triggered sustained release method for DOX delivery using MSNs functionalized with HMAB and capped with a-CD. After the exposure of the neutral solution to UV light at 365 nm, trans-azobenzene undergo cis conformation, dissociating from the a-CD and releasing the cargo, whilst hydrazone connections were destroyed to achieve acid-controlled release. At pH 6.0 and 5.0, respectively, the maximal DOX emission was 57.5 percent and 75.2 percent [57].

The pH-responsive porous -cyclodextrin implants for tumor treatment were synthesized through conjugation with 3-(diethylamino)propylamine (DEAP, a pH-responsive moiety), permitting pH-dependent release of the encapsulated paclitaxel. -Implantation of CD-DEAP microparticles at the tumor site significantly improved tumor cell death in vitro/in vivo, suggesting its potential as a cancer therapeutic implant [58]. pH-responsive nanoplatforms may be readily created using acetylated α-cyclodextrin materials as shown in Figure 2. The hydrolysis time of NPs may be carefully regulated by introducing a variety of easily programmable acetal types into the materials. These pH-modulated hydrolyses and pH-triggered drug delivery NPs exhibit exceptional biocompatibility in cell studies as well as animal studies. By combining the anticancer medication paclitaxel (PTX) with newly discovered pH-sensitive nanosystems, nanotherapeutics with dramatically enhanced cytotoxicity against a variety of tumor cells may be generated. Notably, these nanomedicines can overcome PTX-resistant cancer cells’ multidrug resistance. Additionally, animal studies indicate that pH-sensitive nanosystems outperform pure PTX and pH-insensitive PLGA nanoformulations in anticancer applications. Furthermore, while cyclodextrin-based nanovehicles were compared to two different acid-labile materials, the benefits of cyclodextrin-based nanovehicles were shown in terms of loading capacity, efficacy, and side effect mitigation. These pH-responsive NPs may be used in novel DDSs [59].

Figure 2. The development of a pH-sensitive acetylated α-CD based PTX nanoformulation is shown schematically (Ac-aCD). Reproduced with permission from [59].

Some cancer cells overexpress the mannose-6-phosphate (M6P) receptors (for example, BC), and they have also tangled the endocytosis of M6P labeled proteins to lysosomes. Nanocarriers derived from mannose-6-phosphate glycopolypeptide (M6PGP) that are bioactive and stimuli-responsive have been demonstrated for the first time. They are picked up preferentially by receptor-mediated endocytosis into the lysosomes, where they undergo pH-mediated or enzymatic hydrolysis, therefore releasing the cargo. M6PGP15-APPO44 and M6PGP15-(PCL25)2 are two distinct amphiphilic M6P block copolymers synthesized by a click reaction between alkyne-functionalized M6PGP15 and pH-responsive biocompatible azide-functionalized acetal PPO and branching PCL. Self-assembly of M6P and glycopolypeptide block copolymers into micellar structures in an aqueous medium. These were found to be capable of encapsulating the rhodamine-B-octadecyl ester (hydrophobic dye). At physiological pH, they were stable but disintegrated when subjected to acid (in the case of M6PGP15-APPO44) or esterase (in the case of M6PGP15-(PCL25)2) [60]. These M6PGP-based micellar NPs may be utilized to specifically target lysosomes in malignant cells such as MDA-MB-231 and MCF-7 [60].

2.2. Light responsive

By initiating medicine release using a light source, more control over drug delivery is possible, since light may be easily targeted in small areas, minimizing the potential of therapy-related side effects in nearby zones. Additionally, because of its low toxicity and simplicity of administration, it is one of the most researched stimuli in DDSs. For the first time, Mal et al. showed the use of ultraviolet (UV) light to induce reversible release by blocking the pores of an MSNP with coumarin molecules that undergo reversible dimerization in response to light irradiation [61]. By introducing azobenzene molecules into the pore channels, the same research group increased the system’s behavior. When exposed to UV light, these molecules undergo cis-trans isomerization, enabling them to act as nanoimpellers, ejecting the medications from the pores [62]. CD-modified nanomaterials were synthesized through a chemical coprecipitation process and may be employed as DOX carriers. The addition of carboxyl groups and a β-CD cavity to the surface of the nano system enhanced their biocompatibility and encapsulation capability, as shown by the carrier’s capacity to transport 447 mg/g of medication. When the medicine was exposed to near-infrared light, it was effectively released. Additionally, MTT and confocal imaging studies on Hep-G2 cells established conclusively that the drug cargo was non-cytotoxic and capable of quickly penetrating the cells. These results suggested that the developed nano carrier has significant promise for sustain release and targeted delivery of DOX [63]. By covalently integrating a water-soluble PS and coating their exterior surface with mannose (MN) residues, a novel class of MSNs was produced [62]. After 40 minutes of monophotonic irradiation (630–680 nm; 6 mW cm-2) on MDA-MB-231 cancer cells[63], these MSN had a much better in vitro photo efficiency than unfunctionalized NPs[64]. The supramolecular hydrogel composed of hybrid graphene oxide (GO) and carbon nanotubes (CD) may react to near-infrared light and may be utilized to transport and release anticancer medicines (5-FU). The experimental findings indicate that the GO hybrid supramolecular hydrogel efficiently transforms light into heat. The photothermal activity of near-infrared light influences both the hydrogel’s breakdown and the medication’s release from the carrier [65]. The amphiphile hyaluronan-o-nitrobenzyl-stearyl chain (HA-NB-SC) self-assembled into unique photo-controlled drug-loaded nano micelles encapsulating doxorubicin (DOX) inside the hydrophobic core (Figure 3). When DOX-loaded HA-NB-SC nano micelles are subjected to UV light (365 nm), they may disintegrate, releasing DOX into specified ill regions. Additionally, a combination of nitrosobenzaldehyde derivatives, photo-induced products of HA-NB-SC, and DOX has been demonstrated to suppress HeLa cell growth [66].

Figure 3. Photo-controlled HA-NB-SC nanomicelles for CD44-mediated transport and UV light-triggered intracellular release of DOX in HeLa cells are shown schematically. Reproduced with permission from [66].

Srinivasan et al. described the synthesis and characterization of IR820-chitosan conjugates, revealing them as effectual for usage in diagnostic and therapeutic applications as a multifunctional imaging-hyperthermia NS. 41 When subjected to an 808 nm laser, the IR820-chitosan conjugates generated heat, which reduced cell growth in tumor cells for example the MES-SA, SKOV-3, and Dx5 cell lines [67]. When arylazopyrazole (AAP) was exposed to light, it was determined to be a photosensitive azobenzene molecule (365 nm, 520 nm). This design modification might be used as a toggle switch to regulate the release of certain small molecules. Using AAP as a linker, Davidson-Rozenfeld et al. synthesized a hydrogel from modified cellulose-CD. The experiment demonstrated that by transfiguring the structure of AAP with light, it is feasible to convert it to a cis-structure (365 nm). Photoisomerization of cis-AAP to trans-AAP at a wavelength of = 520 nm, on the other hand, restored the crosslinked -CD/trans-AAP hydrogel. The hydrogel’s strength varied between high- and low-stiffness states over this time. Incessant conversion of ultraviolet and visible light may be used to regulate the release of DOX in drug release studies [68]. A dual stimuli responsive two-dimensional Janus composite nanosheets (JCNs) was made up of gold islands that have been sequentially hetero-grafted with three different biocompatible polymers (gum arabic, chitosan, and poly(ε-caprolactone)-b-polyethylene glycol (PEG-b-PCL)). To synthesize pH- and NIR-responsive JCNs, physical deposition-surface functionalization-chemical exfoliation techniques were applied. They proved that by incorporating GA and chitosan into the material, it gains pH responsiveness, allowing it to expand/contract at low pH values (protonated states) and contract/expand at high pH levels (the non-protonated states). Additionally, PEG-b-PCL was grafted onto the chitosan JCN layer to enhance Dox discharge in response to NIR light. The scientists found that whereas adding Dox self-scrolls the JCNs, NIR stimulation unscrolls them by converting crystalline PCL domains to an amorphous form and afterward unloading the Dox. They determined that the newly developed structure is optimal for tumor phototherapy and chemotherapy, as well as two-photon-induced photothermal tumor imaging [69].

2.3. Temperature-responsive drug delivery

Temperature is another internal signal that may be used to initiate the release of medication or genes at a particular place. For instance, it has been shown that many cancers have a local temperature somewhat higher than normal body temperature. Against this backdrop, an ideal temperature-sensitive drug carrier would release the medication only at temperatures greater than 37°C and encapsulate it throughout blood circulation [70]. The usage of N, N’-bis(acryloyl)cystamine as a biodegradable cross-linking agent resulted in the development of thermosensitive nanogels based on β-CD (Figure 4). It was shown that at elevated/decreased body temperature, the nanogel’s sensitivity to swelling behavior increased dramatically. Remarkably, the nanocarrier can efficiently entrap DOX (79%) and can also be used to remotely release the medication by raising the temperature. Additionally, in vitro analysis revealed the quick absorption of nanogels by KB cells, exhibiting greater anticancer toxicity, indicating their potential for therapeutic drug delivery over anticancer drug delivery [71].

Figure 4. The formation of β-CD-hybridized nanogels (PNAC) through in situ radical polymerization and their drug loading/release characteristics are shown schematically. Reproduced with permission from [71].

Curcumin was also enclosed in another study employing 3-amino propyl triethoxy silane (APTES) functionalized Fe₃O₄ magnetic NPs (MNPs) and coated with Chitosan (CS) and Tragacanth Gum (TG). Further investigation of curcumin’s release properties was conducted at pH 7.4 and 3.4, as well as at 37 and 40 degrees Celsius. The nanocomposite displayed an enhanced ratio of swelling at pH 3.4 and 40°C, as well as pH- and temperature-dependent drug release patterns. They discovered that the resulting nanocomposite might be used as a ‘smart’ carrier in cancer treatment [72].

Using β-CD-immobilized and coated poly (N-isopropylacrylamide) NPs, a unique kind of NPs with a particle size of around 160 nm was effectively created. The efficacy of encapsulating doxorubicin in NPs may reach 92%. Additionally, pH and temperature conditions were revealed to influence the drug release behavior. When the cap was removed from the pores at endosomal pH (pH 5.5), the amount of medicine released increased [73]. The current paper highlights the creation of a system for targeted drug administration employing graphene oxide (GO) functionalized with carboxymethyl chitosan (CMC), lactobionic acid (LA), and fluorescein isothiocyanate. As controllers, comparable systems were constructed without LA. The composites were treated with DOX through adsorption. Both LA-free and LA-functionalized materials exhibited pH-dependent release. While the modified GOs are highly biocompatible with the liver cancer cell, they may induce cell death after 24 h after DOX loading [74]. Magnetic graphene oxide nanocrystals conjugated with pectin (Pectin-GO-Fe₃O₄) were developed for cancer targeting with paclitaxel. The developed nanocrystal possessed outstanding capability in terms of drug loading, biocompatibility, and pH-responsive release. The pH-responsive release analysis of the nanohybrid discovered that it released more drugs at the endosomal pH of the cancer cell rather than physiological pH.[75]. This study successfully encapsulated iron oxide (Fe₂O₃) NPs and doxorubicin (Dox) into natural almond gum hydrocolloids through an antisolvent precipitation method. The cubic Fe₂O₃ crystal structure of the generated iron oxide NPs was validated using X-ray diffraction and X-ray photoelectron spectroscopy. IODPC NPs were shown to be more sensitive to acidic pH and to display Higuchi diffusion kinetics during drug release. In vitro uptake and viability of IODPC NPs were investigated using HeLA cell lines. The greatest levels of doxorubicin were seen at an acidic pH (5.5), supporting their pH-sensitive action. Due to the hyperthermic potential and pH responsiveness of the synthesized IODPC NPs, they may be employed as a multifunctional DDS for tumor treatment [76]. Another technique identified curcumin-specific DDS in the colon as GMA-modified GA that is pH-responsive. They examined the curcumin release kinetics in both simulated intestinal fluid (SIF, pH 6.8) and simulated gastric fluid (SGF, pH 1.2), and discovered more responsive beviour to SIF than to SGF. Additionally, they observed that varying the GMA concentration alters the characteristics of gels, ranging from weak to dual-responsive gels [77]. A previous have developed pH-responsive magnetic hydrogels based on TG for application in the treatment of solid tumors with chemo/hyperthermia. MTT tests on Hela cells indicated that the combination of chemotherapy and heat treatment was somewhat more effective than chemotherapy alone in vitro therapeutically. These results suggested that nanostructures may be utilized in cancer treatment as ‘smart’ DDSs [78]. Shafiee et al. coated CS and TG-capped MNPs with APTES to generate a pH/temperature-responsive to deliver the curcumin. They observed a greater swelling proportion at low pH owing to the protonation of the amino groups in chitosan. Additionally, a larger swelling ratio was detected at elevated temperatures, attributing to the dissolution of intramolecular hydrogen bonds and enhanced water penetration into the nanocarrier. Curcumin release was examined at two different pH values of 7.4 and 3.4, as well as at 37 and 40°C. The higher swelling ratio of nanocomposite at pH 3.4 and 40°C, as well as pH- and temperature-dependent drug release patterns. They concluded that their nanocomposite may be used to deliver cancer treatment in a ‘smart’ manner [72].

2.4. Magnetic field responsive

Due to their improved imaging and biocompatibility, superparamagnetic iron oxide NPs have garnered considerable attention in cancer imaging, diagnostics, and therapy (approved by the US Food and Drug Administration). Using metal-adhesive dopamine groups, CD may create covalent bonds with superparamagnetic iron oxide NPs. Polyethylene glycol (PEG) and paclitaxel were introduced into the β-CD cavity of the synthesized NPs through non-covalent contact (Figure 5). These substances are used to treat cancer. When the polymer is administered intravenously to the mouse, it is acculated to the appropriate location by an external magnetic field. During the nano assembly process, superparamagnetic iron oxide NPs may allow speedy and effective targeted medicine delivery. In both in vivo and in vitro studies, the nano assembly generated demonstrated increased anticancer activity when compared to a control group [79].

Figure 5. Overall experiment depicting the use of pPTX/CD-SPION nano assembly for magnetically guided delivery of drugs in anticancer treatment. Reproduced with permission from [79].

In another study, the researchers showed a simple approach for coating magnetic iron oxide NPs (GA-MNPs) with GA for use as cancer therapy agents. They showed that GA adsorbed onto MNPs as a result of the GA structure’s different charged groups (carboxyl and amine). Adsorbed GA acts as a steric barrier to the coagulation of MNP and also supplies orientated functional moieties that are excellent for bioconjugation. Additionally, the authors used a model drug, rhodamine B. They demonstrated that their magnetic nano complex remained stable in physiological media and was rapidly absorbed by 9 L glioma cells. GA-MNP accumulated 12-fold more in brain tumors than in the healthy brain, according to in vivo magnetic targeting tests. MRI was used to visually examine the stated selectivity in tumors [80].

2.5. GSH/ redox responsive

Additionally, an imbalance of reductive species (e.g. glutathione [GSH]) between the exterior and inside of cells, as well as between normal and malignant tissues, is an internal trigger. There is 1000 times more reduced GSH inside the cell than there is in the extracellular medium. Because cancer cells have a high concentration of GSH, several nanocarriers have been reported with GSH-responsive behavior and cleavable disulfide linkage for targeted delivery and cell imaging [81–83]. They demonstrate that a chlorambucil-based amphiphilic prodrug including a fluorescent reporter and a d-MN-targeting ligand may self-assemble directly into GSH-responsive nanovesicles for intracellular imaging and cancer treatment. These nanovesicles may burst after being internalized in MCF-7 cancer cells overexpressing the d-MN receptor, releasing the chlorambucil medication with unique crimson light. Additionally, the nanovesicles demonstrated increased selectivity and therapeutic effectiveness when compared to free chlorambucil [84].

Due to their role in receptor-mediated endocytosis, glycopolypeptide-based NPs are an intriguing drug carrier. Stable bioactive dual-stimuli-responsive (enzyme and redox) micelles based on glycopolypeptide were synthesized as shown in Figure 6 for the selective delivery of cancer therapeutics to tumor cells. BADS conferred redox-responsive behavior, whereas PCL provided the enzyme-degradable potential to the micelles. When both redox and enzyme stimuli were delivered to the ICL micelles alone, a synergistic and programmed action resulted in significantly enhanced doxorubicin (Dox) release. Cytotoxicity studies established the non-toxic behavior of nascent ICL and UCL micelles (80% viability at 300 g/mL) and that ICL micelles delivered Dox more specifically to HepG2 cells than UCL micelles. In Case 1, after a redox stimulus, about 38% Dox release was observed after 22 hours and an additional 40% release after 26 hours with the introduction of a second stimulus (esterase enzyme), for a total of 78% released after 48 hours. Using just redox as a stimulant resulted in a 56 percent total drug release after 48 hours. Consequently, once ICL micelles are subjected to both stimuli concurrently, they release 22% more Dox than when just redox is utilized [85], most likely owing to a greater percentage of micellar breakdown.

Figure 6. Synthesis and Self-Assembly of Amphiphilic Star Co-Glycopolypeptides into Uncross-Linked (UCL) and Interface Cross-Linked (ICL) Micelles for Targeted and Controlled Drug Delivery. Reproduced with permission from ACS 2019 [85].

MDR elimination has the best potential of success if nanoscale carriers capable of collecting and delivering medications intracellularly are developed. These nano micelles facilitate medicine targeting, accumulation, and retention in MDR tumor cells [86].

The development of a new dual-responsive redox/pH multifunctional magnetic complex micelle (sPEG/HA/CSO-SS-Hex/Fe₃O₄/GA) for the parenteral administration of gambogic acid (GA) and Fe3O4 NPs in the treatment of triple-negative breast cancer (TNBC). When magnetism-EPR was used to expose the magnetic complex micelle to 10 mM GSH, the micelle remained relatively stable in healthy conditions but quickly deconstructed to release drug loads and was preferentially taken up by tumor cells through endocytosis mediated by HA-receptor. As a consequence, tumor-targeted GA delivery through the redox/pH dual-responsive sPEG/HA/CSO-SS-Hex/Fe3O4/GA may have therapeutic implications for TNBC [87].

In another study, authors co-encapsulated an immunogenic cell death (ICD) inducer DOX and an IDO inhibitor 1-methylDL-tryptophan (1MT) into a polypeptide nanogel of methoxy poly(ethylene glycol)-poly(L-phenylalanine-co-L-cystine) (mPEG-P(LP-co-LC)) termed NG/(DOX+1MT) with reduction-responsive characteristics for 4T1 breast cancer treatment. The anticancer drugs were released simultaneously to tumor cells via a reduction-responsive polypeptide nanogel. After therapy, Treg and MDSC recruitment was suppressed, and the frequency of tumor-infiltrating CD8 + T cells was dramatically increased. There were no obvious side effects from the chemoimmunotherapy method, showing that it has significant potential for use in clinical cancer therapy [88].

2.6. Enzyme responsive

Enzymes are very efficient and highly specific when they interact with substrates in the human body. As a consequence, researchers studied whether the technology might be used to modify the delivery and release of medications. Numerous particular enzymes (for example, proteases, phospholipases, and glycosidases) are overexpressed in cells under pathological circumstances such as cancer or inflammation. It is now conceivable to manufacture enzyme-mediated drug release as a result of this finding [89]. A previous study reported the direct synthesis of a new enzyme-responsive supramolecular assembly employing biocompatible sulfato-b-cyclodextrin (SCD) [90]. The authors present two glucose-based intelligent tumor-targeted DDSs in combination with an enzyme-sensitive release technique. On magnetic NPs, the carrier molecules CMS and β-cyclodextrin (β-CD) were grafted (Fe₃O₄). Because prodigiosin (PG) preferentially targets aggressive tumor cells, it was selected as the model anti-tumor agent. The anticancer agent prodigiosin (PG) was encapsulated into the NPs with an encapsulation efficiency of around 81 percent for the β-CD-MNPs and 92 percent for the CS-MNPs. After one hour of incubation with numerous enzymes (hydrolase, amylase, and chitosanase), it was revealed that the maximum quantity of medications (58.1 percent) was released. Cytotoxicity tests using MCF-7 and HepG2 cancer cells, as well as non-cancerous NIH/3T3 cells as a control, indicated that drug-loaded NPs kill cancer cells more efficiently [91].

Amoros and colleagues synthesized one-of-a-kind capped SMPs by dye loading and then functionalizing them with hydrolyzed starch and lactose derivatives. With the addition of galactosidase, DOX release was greatly increased, and the final system exhibited effective internalization and cellular uptake in HeLa cells [92]. To develop a colon cancer-specific treatment, guar gum-based matrix tablets were loaded with curcumin. This research revealed that the presence of more guar gum in the tablets results in more intact therapeutic ingredients that would stay throughout transit. Indeed, tablets containing 40% guar gum released 91% of the active ingredient during 24 hours, whereas tablets containing 50% guar gum released 8%. In vitro, guar gum is vulnerable to the enzymatic activity of rat caecal contents, resulting in increased drug release when rat caecal contents are introduced. As a result, guar gum may be utilized to provide colon-specific drugs [93]. Stable biomimetic vesicles consisting of M6P lipid are capable of encapsulating and delivering dual dye/drug and protein/enzyme to the lysosome in HEK-293 cells. Temporally controlled cargo release from vesicles may be possible as a result of the morphological change in the M6P lipid assembly in response to the enzyme. Fluorescence spectroscopy demonstrated a 7% dye/drug release in the absence of esterase enzyme after 50 hours of incubation at two distinct pH values (PBS, pH = 7.4 and 5.0, 37°C). While after 50 hours in the presence of the esterase enzyme at a pH of 5.0, the anticancer medication DOX released 60% of its total concentration [94]

MTX and MAN were conjugated in this work through a hydrolyzable ester link to generate an MTX–MAN conjugation as a single molecule that self-assembled instantly. Through a combination of lysosomal acidity and esterase activation, these carrier-free MTX–MAN NPs with a precise drug–sugar ratio may allow on-demand drug release. Due to their unusual dual-recognition affinity, the MTX–MAN NPs were promptly and preferentially taken up by FA/LT receptor-overexpressing tumor cells once they reached the tumor site. Furthermore, systematic in vitro and in vivo research established that the MTX–MAN NPs demonstrated superior treatment effectiveness and biosafety [95].

2.7. Ultrasound response

Ultrasounds are an efficient tool for spatiotemporal regulation of drug release at the specified site, hence avoiding adverse effects on healthy tissues. Ultrasounds are especially appealing owing to their non-invasive nature, the absence of ionizing radiation, and the ease with which tissue penetration depth may be adjusted by adjusting frequency, duty cycle, and exposure time [96]. The drug can be released from a variety of nanocarriers by cavitation processes or radiation forces induced by ultrasound waves. Since cavitation can generate nanocarrier instability, drug release [97], and an increase in vessel permeability, resulting in therapeutic molecule uptake by the cells [98].

Meng et al synthesized the doxorubicin-loading O carboxymethyl chitosan nanodroplets for drug delivery application in vitro (Figure 7) [99]. With ultrasound exposure (1 w/cm2) at 37◦C for 10 min, 73.6%)of the drug was released from the nanodroplets while it was only 0.59% without ultrasound exposure. The nanodroplet significantly lowers the cell viability of PC-3 cells in the O-CS-DOX NDs group than that in the DOX group with ultrasonic irradiation suggesting the improved anticancer efficacy of DOX owing to ultrasound responsive drug release.

Figure 7. Ultrasound-triggered drug release from targeted nanoparticles. The controlled ultrasound beam is focused on the tumor tissue; nanocarriers passing through the high-intensity focused beam are disrupted or activated. Reproduced with permission from [116].

Table 1 illustrates the various Carbohydrate based stimuli-responsive nanocarriers for cancer treatment.

Chitosan-alginate nanoparticles were made in another study and employed with an ultrasound approach to accomplish high-efficiency gene transfection of the pAcGFP1-C1 plasmid [100]. Enzymatic digestion of the DNA was prevented and gene transfection efficiency was increased in HeLa cells and 293 T cells by the synthesized nanoparticles. Exposure to an Ultrasound regimen, either in vitro or in vivo, further enhanced the effectiveness of gene transfection. Although ultrasound reduced cell viability, the simultaneous use of gene transfection and tumor destruction by focused ultrasound may have benefits for cancer gene therapy.

3. Applications of carbohydrate-based nanoparticles

Glycan alterations in malignant cells, a cancer hallmark, manifest themselves in several ways: increased expression of truncated or incomplete glycans, excessive expression or loss of expression of various glycans, and, less commonly, the development of new glycans (26, 74). Additionally, G-NPs have been examined for their potential to enhance the precise delivery of existing and novel medicines, as well as proteins, DNA, and peptides such as vaccines. A database search was conducted using the terms ‘glycoconjugates,’ ‘glycopolymers,’ and ‘glycodendrimers’ in Scopus and Integrity (https://integrity.clarivate.com/integrity/xmlxsl/) indicated increasing research on G-NPs over the past two decades (about 3,500 patents), which is particularly noteworthy given that the technology patents globally has increased to double in the previous decade. As a result, these nanosystems may be exploited in cancer therapy and prevention, pathological imaging diagnostics, and prognostics.

3.1. Carbohydrate-based nanoparticles as carriers of drugs and small molecules

The frequently used strategies for cancer treatment involve the utilization of small molecule drugs, and NP to improve their pharmacodynamic pharmacokinetic profiles by maintaining the NPs in circulation for a longer period, increasing biodistribution along with circulation of the drug, and decreasing in vivo side effects [101]. For example, GLUT overexpression in BC cells has been shown to improve medication absorption [102]. A therapeutic approach that incorporates glycosylation of methotrexate-loaded PAMAM dendrimer in a single step (OS-PAMAM-MTX-GLU) was also developed. This research has shown that glucose conjugation increased the internalization of OS-PAMAM conjugates by 150 percent in MDA-MB-231 BC cells and decreased cell survival by up to 20%. Cancer cell mortality was dramatically increased when the nanosystem was used instead of free MTX, and the system exhibited specificity since no impacts on noncancer cells were found.

Additionally, other techniques have been published, including two glycosylated delivery systems for cisplatin (CDDP), mannose-decorated tobacco mosaic virus (CDDP@TMV-Man), and lactose-decorated tobacco mosaic virus (CDDP@TMV-Lac). CDDP@TMV-Man significantly increased endocytosis and death in galectin-rich MCF-7 cells, while CDDP@TMV-Lac significantly increased endocytosis and apoptosis in HepG2 cells overexpressing asialoglycoprotein receptors (ASGPR) [103].

3.2. Carbohydrate-based nanoparticles as carriers of nucleic acids

Owing to recent advancements in gene therapy, G-NPs have been used to transfect particular nucleic acids (siRNA, DNA, and miRNA). A human non-small cell lung cancer cell line was exposed to a variety of cationic block copolymers (PHML-b-PMAGal) and statistical copolymers P(HML-st-MAGal) containing natural moieties such as galactose and (L-)-lysine. Among the produced cationic polymers, P(HML40-st-MAGal4), with a galactose concentration of 4.8 percent, had the best efficacy of gene transfection, 6.8-fold more than the ‘gold standard’ bPEI-25k [104]. Combinatorial therapies, such as the use of targeted NPs to deliver chemopeptides and gene therapeutics, revealed the efficient delivery of chemopeptides and gene therapeutics to cancer site, avoiding systematic cytotoxicity, defeating drug resistance, and halting the development of tumor. In one work, a new mannosylated copolymer with a CPP grafted onto Polyethylenimine (PEI) was developed to target MN receptor-expressing antigen-presenting cells (APCs). The grafted CPP mannosylated cells transfected substantially more genes than control cells [105].

3.3. Carbohydrate-based nanoparticle applications in immunotherapy and vaccines

On cancer cells, altered glycans can be considered as a diagnostic and tumor cell marker [106]. Not only have glycan aberrations been employed as markers, but they may also be associated with endogenous lectins, including galectins, sialic acid-binding immunoglobulin type lectins, and selectins [107]. Type C lectin receptors, for example, are highly expressed on myeloid cells (i.e. neutrophils, macrophages, and dendritic cells. As a result, they may enhance tumor rejection by mediating particular interactions with tumor antigens [108,109]. Due to their importance, incomplete or truncated glycan structures have been examined. These structures are frequently coated with sialic acid and are usually referred to as tumor-associated carbohydrate antigens (TACA) [110]. These antigens are overexpressed in numerous cancer types, including breast, pancreatic, bladder, and colon [111]. For example, glycodendrimers were investigated for their dual targeting characteristics utilizing a melanoma antigen (gp100) directed by CD4 and CD8 and a glycan (LeY) recognized by type C lectin receptors DC-SIGN and Langerin. Thus, the first glycovaccine targeting dual C-type lectin receptors (CLR) was developed using glycosylated dendrimers, which penetrated multiple human skin DC and enhanced antitumor CD8 + T cell responses [112]. These studies suggest that glycans may be used to design systems for detecting biomarkers for tumor diagnosis and prognosis, as well as vaccinations targeting carbohydrate antigens [107].

3.4. Carbohydrate-based nanoparticles used in theranostics

The Warburg effect is a defining characteristic of cancer and is used to target both diagnostic and treatment efforts [113]. Numerous glycoconjugates, including 99 mTc-labeled deoxyglucose derivatives and glucosamine functionalized with multiwall carbon nanotubes, have been used as diagnostic agents for heart and brain tumors and shown better accuracy than currently used approaches [114]. However, in recent years, theragnostic systems, such as silica and hyaluronic acid-based NPs that can be used to image cancer cells while also suppressing tumor growth, have been developed by increasing the solubility of hydrophobic drugs and glycosylation-mediated drugs, as well as the tumor cell targeting efficiency, with the least possible toxicity [115].

4. Expert opinion

Chemotherapeutic agents, either alone or in combination with other treatment modalities, are currently widely used for the treatment of various types of cancers. However, anticancer drugs are highly non-specific for cancerous cells. The therapeutic concentration in the tumor microenvironment for anticancer drugs is achieved at the expense of extensive contamination of the rest of the body, thus leading to diverse off-target side effects. Therefore, nanocarriers are explored as an alternative and efficient strategy for targeted and site-specific delivery of anticancer drugs. Stimulus-responsive nanocarriers are designed in a way that they respond to exterior stimuli like ultrasonic, light, heat, and magnetic fields, along with various internal stimuli including pH, hypoxia, enzyme, redox potential, thus releasing their loaded anticancer agents specifically in the micro-environment of the tumors. This in turn leads to the increased concentration of the drugs in the proximity of the tumor while avoiding the non-specific distribution of the drugs in other healthy tissues. Thus, stimulus-responsive nanocarriers achieved higher therapeutic efficacy for the anticancer drugs with minimum off-target side effects.

Carbohydrates based stimulus-responsive nanocarriers are currently getting wider acceptance for cancer-targeted chemotherapy due to their chemical versatility, inherent multiple functionalities, capabilities of forming nanocarriers of diverse shape and size, low cost, increased drug loading and biocompatibility, and having diverse sugar moieties and functional groups that can be employed as targeting ligand for targeted delivery of anticancer drugs. Carbohydrate-based nanocarriers offer a novel approach for the targeted delivery of anticancer drugs to tumors. They offer high specificities and multiple drug delivery capabilities, such as altered tumor accumulation, regulated release, tumor accumulation, switch ‘ON-OFF’ activities, and improved diagnostic and therapeutic accuracy and efficacy. Currently, various carbohydrate-based stimulus responsive nanocarriers surface modified with targeting ligands have been designed and developed for tumor-specific delivery of anticancer drugs and genetic materials. Thus, improved clinical efficacy with minimized side effects has been achieved at low doses of the drugs loaded. Further, carbohydrate-based stimulus responsive nanocarriers have also been reported for targeted combination therapy of various types of cancers, thus resulting in highly safe synergistic effects of the co-delivered drugs/antibodies under their selective delivery potentials. Controlled release of their anticancer agent’s payloads in the tumor vicinity for a long time is another striking feature of these stimulus-responsive nanocarriers, this, in turn, leads to the improved therapeutic efficacy of the drugs at a single dose.

Although significant progress has been made in the development of stable carbohydrates-based stimulus responsive nanocarriers for efficient chemotherapy, their real-time applications remain a challenge. Thus, they are still transitioning between labs and clinics. The scalability and physical, chemical, and biological stability of such nanocarriers have still not been efficiently addressed. Further, the heterogeneous nature of the tumor microenvironment is a real challenge that cannot be effectively overcome, thus most of the carbohydrate-based stimuli-responsive nanocarriers fail to efficiently respond to the anticipated/targeted stimulus. This leads to the failure of these nanocarriers to release the loaded drugs in effective therapeutic doses. Nevertheless, the research on carbohydrate-based stimuli-responsive nanocarriers is somewhat at the initial stages, and the scientists are further improving these nanocarriers via surface modification strategies. Researchers are also trying to optimize the preparative conditions/parameters so these nanocarriers can be prepared on an industrial scale. More extensive work is indeed needed in pre-clinical trials so their anticipated stimuli-responsive targeted drug delivery/tumor microenvironment accumulation can be authenticated in face of the harsh and heterogeneous environment of the tumor.

Article highlights

• Chemotherapy is mostly associated with off-target side effects such as nephrotoxicity, and neurotoxicity

• Carbohydrate-based nanoparticles are novel nanocarriers used for targeted drug delivery

• Carbohydrate-based nanocarriers are preferred for targeted delivery due to their unique inherent targeting properties

• Stimuli-responsive nanomaterials release the drug under the influence of various stimuli

• Carbohydrate-based stimuli-sensitive nanocarriers are ideal for cancer-targeted chemotherapyThis box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Zhejiang Provincial Natural Science Foundation of China (No. Y22H168138 to CW Zhang), Zhejiang Provincial Medical and Healthy Science and Technology Projects (No. 2021KY045 to CW Zhang, and 2022KY538 to ZY Lv).