A review on dendrimer-based nanoconjugates and their intracellular trafficking in cancer photodynamic therapy

Figures & data

Figure 1. Schematic representation of active and passive targeted drug delivery in anticancer therapy – reprinted from reference [63], copyright 2023, Springer Nature.

Table 1. Types of mechanisms in which dendrimers penetrate tumour cells.

Type of dendrimer	Name mechanism	Preparation of dendrimers	Targeting and drug release mechanisms
G4 PAMAM dendrimer	Micropinocytosis	Bioconjugation	The PAMAM-NH2 modified with FITC on the amine group surface indicated the uptake pathway, micropinocytosis to be more essential in MCF-7/ADR cells than in MCF-7 cells. PAMAM-NH2 accumulated and degraded more in the MCF-7/ADR cell’s lysosomal vesicles than in the MCF-7 cells. MCF-7/ADR cells were shown to exocytosis PAMAM-NH2 dendrimers [83,84]
G5 PAMAM dendrimer	Clathrin-mediated endocytosis	Surface acetylation	Carbon dots with anionic terminus and cationic acetylated G5 poly(amido amine) containing epirubicin (CQDs@EPI⊂G5-Ac85) hybrids may be internalized by clathrin-mediated endocytosis due to their positive charge overall. The internalization of CQDs@EPI⊂G5–Ac85 hybrids destabilizes membranes and generates ROS, activating a mitochondrial/intrinsic apoptotic pathway. EPI therapy induces transcriptional activation of the p53 gene, which is critical for inducing death in tumor cells [85].
LA-mediated targeting	G5 PAMAM dendrimer	Covalent conjugation	The LA-modification of dendrimers allows for selective targeting of both G5. NHAc-FI-LA/DOX and G5. NHAc-FI-PEG-LA/DOX complexes to ASGPR-overexpressing liver cells, resulting in greater toxicity and faster drug release to the target cells than non-targeted dendrimer/DOX complexes [81].

CQDs: carbon dots; EPI: epirubicin.

Figure 2. In vitro fluorescence or confocal imaging of dendrimer-based nanoparticles in cancer cells. (i) Confocal images of SH-SY5Y cells incubated for 20 min with curcumin/resveratrol/dendrimer NPs – reprinted from reference [89], copyright 2022, ACS publications; (ii) sugar-conjugated dendrimer localizations in glioblastoma – reprinted from reference [90], copyright 2021, Elsevier; and (iii) PEGylated bis-indolyl G2 and G3 polyurethane dendrimer treated cells (A) MDA-MB-231 cells and (B) A549 cells – reprinted from reference [91], copyright 2021, Elsevier.

Figure 3. In vivo MRI images of dendrimer-based NPs in cancer model (i) (a) the coronal MRI images shows the location of U-251 glioma tumour, (b) distribution of G3-curcumin in organs and (c) fluorescence images of kidney (K), spleen (Sp), liver, heart (H), lung (L) and brain and (B) in rat model – reprinted from reference [92], copyright 2016, PubMed Central; and (ii) G5-Gd trastuzumab and G5-Gd NPs injected tumour bearing mice model – reprinted from reference [93], copyright 2020, Springer Nature).

Table 2. Fundamentals of dendrimer-based nanoconjugates for tumour elimination.

Dendrimer nanoconjugates	Model used	Size	Receptor	Outcomes
G3 PAMAM dendrimer, arginylglycylaspartic acid (RGD), AuNSs (gold nanostars) and siRNA.	U87MG tumours (Human Brain cancer)	52.2 ± 14.2 nm	${\alpha }_v{\beta }_3$	The targeting specificity of Au NSs modified G3 PAMAM dendrimers with cyclin RGD peptide to ${\alpha }_v{\beta }_3$ integrin overexpressing U87MG cells resulted in the effective vector delivery of specific siRNA to U87MG cells [97].
FA-PAMAM dendrimer	HN12 and HN12-YFP cells (human head and neck cancer)	5.4 nm	Folate receptor α (FRα)	In a HN12 xenograft tumour model, FR-targeted PAMAM dendrimer G4 complexed with siVEGFA resulted in significant tumour uptake and tumour suppression. Tumour suppression was related to increased tumour absorption of siRNA for head and neck cancer localized targeted treatment [98,99].
G5 PAMAM dendrimer-entrapped CuS NPs (CuS DENPs), (pDNA-HIC1).	MDA-MB-231 tumours (human breast cancer)	4.2 nm	${\alpha }_v{\beta }_3$	RGD-CuS specifically targets MDA-MB-231 cells that express allowing serum-enhanced administration of pDNA-H1C1 to prevent cancer cell migration [100].
G5 PAMAM dendrimers were sequentially modified with fluorescein isothiocyanate (FI) and PEG-linked LA (lactobionic acid)	HepG2 cells (liver cells)	2.7 nm	Asialoglycoprotein receptor (AGSPR)	The modification of LA to dendrimers allows for the selective targeting of both G5. NHAc-FI-LA/DOX and G5. NHAc-FI-PEG-LA/DOX complexes to ASGPR-overexpressing liver cells being more toxic to the cell [81,101].
G5 PAMAM dendrimer encapsulated nanoparticles (DENPs), including CuS, Pt and palladium NPs.	MDA-MB-231 tumours (human breast cancer)	5 nm	${\alpha }_v{\beta }_3$	RGD peptide can selectively bind to MDA-MB-231 cells that overexpress ${\alpha }_v{\beta }_3$ integrin, increasing cellular absorption of RGD-modified dendrimers [102].

CuS: copper sulphide.

Figure 4. [a] Biodegradation and [b] Clearance properties of a dendrimer.

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Data availability statement

Data are openly available in a public repository that issues datasets with DOIs.