PLGA-based biodegradable microspheres in drug delivery: recent advances in research and application

Figures & data

Table 1. Effects of PLGA composition on particle size, drug loading, and release profile of microspheres.

Encapsulated drug	PLGA	Particle size	EE%	Release profile	References
Ciprofloxacin HCl	Different PLGA feeding amount in 5 ml of Acetonitrile, viz 100, 200, 400 mg	42.3, 59.7, and 62.2 μm respectively	EE% of 90.0, 93.8, and 95.3% respectively, positive correlation with PLGA concentration	The drug release rate was decreased	(Jeong et al., 2008)
Etanidazole	The concentration of PLGA in the organic solvent (Ethylacetate or DCM) from 1% to 7% (w/v)	Ethyl acetate(EA): hardly varies with the polymer concentration, except for the polymer PLGA 50:50 DCM: particle size increased with increasing polymer concentration	EE% generally decreases with increasing polymer concentration EA can achieve EE% higher than DCM	Increasing polymer concentration can prolong the release duration DCM always achieves a faster release rate than EA	(Wang & Wang, 2003)
	In the order of PLGA 50:50, PLGA 65:35, and PLGA 85:15	The particle size decreased	–	The release rate of microspheres decreased
Ganciclovir(GCV) and its lipophilic prodrug (GCVMB)	In the order of PLGA 50:50 and PLGA 65:35 (MW: 45,000–75,000 Da)	GCV: 75.9 ± 1.6 and 85.8 ± 1.5 μm respectively. GCVMB: 65.9 ± 1.0 and 69.7 ± 1.1 μm respectively	GCV: EE% of 88.7 ± 0.86 and 91.3 ± 0.54% respectively GCVMB: EE% of 81.7 ± 0.25 and 85.5 ± 0.67% respectively	Both: PLGA 65:35 degrade at a slower rate as compared to PLGA 50:50	(Janoria & Mitra, 2007)
Doxorubicin (Dox)	In the order of PLGA 50:50 and PLGA 75:25	363.1 and 361.4 nm respectively	EE% of 48.37 and 38.65% respectively	The released drug from PLGA 50:50 NPs and PLGA 75:25 NPs were 70.98 and 62.22 % of the entrapped released drug in 20 days of study	(Amjadi et al., 2012)
Vincristine sulfate (VCR) and Quercetin (QC)	PLGA 50:50 (MW: 15 KDa and 17 KDa), PLGA 70:30 (MW: 15 KDa, PLGA 75:25 (MW: 15 KDa and 17 KDa) The concentration of PLGA in an acetone dichloromethane mixture from 10 to100 (mg/ml)	VCR and QC both have a positive correlation with the molecular weight of PLGA and PLGA concentration.	VCR and QC both have a positive correlation with the molecular weight, concentration, and ratio of PLGA	–	(Song et al., 2008)
Doxycycline Hyclate	PLGA 50:50 with different end group, i.e., Purasorb®PDLG 5002,/5002 A (MW: 17 KDa), and 5004/5004 A(MW: 44 KDa)	The average size of around 1 µm, regardless of the end group and molecular weight of PLGA	The microspheres made from PLGA with a high molecular weight and ester end group showed a significantly higher encapsulation efficiency	A drug release within 42 days of approximately 92%, 89%, 47%, and 43% for PDLG 5002 A, 5004 A, 5002, and 5004, respectively	(Wang et al., 2019)

PDLG 5002/5004 with the ester end group; PDLG 5002 A/5004A with the acid end group.

Figure 1. A diagram of PLGA-based biodegradable microspheres in drug delivery.

Figure 2. Schematic of PLGA microspheres prepared via (a) single emulsion and (b) double emulsion.

Figure 3. Schematic of microfluidic devices for making PLGA microspheres. (a) T-Junction microfluidic device, (b) co-flow microfluidic device, (c) flow-focusing microfluidic device.

Figure 4. (a) Schematic of a microfluidic parallelization device containing 8 double emulsion drop makers. Hydrophobic channels (indicated in red) and hydrophilic channels (indicated in blue) are located on different layers of the device. Inset shows the simultaneous operation of two adjacent drop makers of the parallel chip. (b) Photograph of the parallelized microfluidic device. Adapted with permission from Reference (Nawar et al., 2020). Copyright 2020, Royal Society of Chemistry.

Figure 5. Schematic of the electrospray process for preparing PLGA microspheres.

Figure 6. Schematic diagram of the spray drying process.

Table 2. PLGA-based biodegradable microspheres for cancer drug delivery.

Drugs	PLGA composition	Preparation method	Sustained drug release	Cell model	Animal model	Cancer	References
Verteporfin	PLGA 50:50 (MW: 7-17 KDa) and PLGA 85:15 (MW: 190-240 KDa)	O/W emulsification	–	GBM1A, IOMM-LEE, KT21-MG1, JHC7, IOMM LEE , and KT21-MG1 cells	GBM xenograft model (male nude mice)	Intracranial tumor	(Shah et al., 2019)
Paclitaxel	PLGA 75:25 (MW: 24483)	W1/O/W2 emulsification	12 days with a cumulative release of 85%	U251 cells	Human liver carcinoma xenograft model (BALB/c-nu mice)		(Zhang et al., 2018)
Camptothecin/rvincristine	PLGA 75:25 (MW: 14400)	W1/O/W2 Emulsification	CPT: 72.5% (28 days) VCR: 54.5% (28 days)	–	Rat glioma models		(Ozeki et al., 2012)
Quercetin	PLGA 50:50	O/W emulsification	PH7.4：the amount of quercetin release was 67.81% in 12 h PH5.3：a cumulative drug release percentage of 72.21% in 12 h	THP-1 cell lines and MCF-7 lines	–	Breast cancer	(Karthick et al., 2019)
Curcumin	PLGA 50:50	O/W emulsification	–	–	A transgenic mouse model of HER-2 cancer		(Grill et al., 2018)
Doxorubicin	PLGA 50:50 (MW: 10000)	W1/O/W2 emulsification	–	The mouse breast cancer cell line 4T1	4T1 tumor model (female BALB/c nude mice)		(Fang et al., 2015)
Doxorubicin hydrochloride	PLGA (MW: 54,600 Da)	Coaxial electrostatic spray	A cumulative release amount of over 80% in 21 days	Endothelial cells and 4T1 cells	4T1 tumor model (female BALB/C mice)		(Ni et al., 2020)
Doxorubicin	PLGA 50:50 (RG 503,MW: 33,000 Da)	Electrospray	A cumulative release amount of 85.8 % after 30 days	–	Male Sprague Dawley rats	Tumor	(Hsu et al., 2020)
Camptothecin	PLGA (MW: 24,000 Da)	W1/O/W2 emulsification	—	HeLa cancer cells	–	Cervical cancer	(Ayyanaar et al., 2019)
7-Eth-10-hydroxy camptothecin	PLGA 50:50 (MW: 15,000)	O/W emulsification	—	–	H22-bearing KM mice (female Kunming mice)	Tumor	(Hao et al., 2019)
5-fluorouracil	PLGA 50:50 (MW: 47 KDa)	S/O/Ho method	One month	–	Male rabbits with colon tumors and adult male Sprague Dawley (SD) rats	Colon tumor	(Lin et al., 2014)

Figure 7. (a) The SEM micrographs of smooth PTX-PLGA-MS. (b-d) The SEM micrographs of rough PTX-PLGA-MS and the arrows represent the PTX drug substances. (e) In-vitro cumulative released curves of free PTX and PTX-PLGA-MS. (f) In-vitro evaluation for apoptosis when PTX formulations co-cultured with U251 cells. (g) Tumor growth curves of smooth or rough PTX-PLGA-MS, PLGA-MS, free PTX, and with no treatment during the entire experiment. (h) Tumor weight of each treatment group at the end of the tests. Adapted with permission from Zhang et al. (2018). Copyright 2018, Informa UK Limited.

Figure 8. The SEM micrographs of PLGA (a-b) and Quercetin-loaded PLGA (PLGAq) microspheres (c–d). (e) In-vitro cumulative released curves of PLGAq under normal and tumor microenvironment. (f) In-vitro cytotoxicity assay tested using THP-1 cell lines. (g) In-vitro cytotoxicity of PLGA and PLGAq tested on MCF-7 cell lines. Adapted with permission from Karthick et al. (2019). Copyright 2019, Elsevier.

Table 3. PLGA-based biodegradable microspheres for protein or peptide drug delivery.

Drugs	PLGA	Preparation method	EE%	Initial burst rate	Cell model	Animal model	References
Exenatide	PLGA 50:50 (Resomer 503H)	W1/O/W2 emulsification	61.6 ± 0.6%	13.3 ± 0.8%	–	–	(Park et al., 2019)
Octreotide acetate	PLGA (Mw: 2.4–3.8 KDa, free carboxylic acid)	S/O/W emulsification	90%	3.56%	–	Sprague-Dawley Male Rats)	(Liu et al., 2019)
BSA or rabbit anti-laminin antibody-protein	PLGA 50:50 (MW: 38–54 kDa) and sodium alginate	W1/O/W2 emulsification	5% PLGA/3% sodium alginate：75.65% 5% PLGA/3% sodium alginate：74.43%	Reduced by 27% compared to without sodium alginate	RSC96、MC3T3-E1 Subclone 4, and L8 cell line	–	(Zhai et al., 2015)
Triptorelin	PLGA 75:25 (MW: 12KDa) with the different concentration, such as 2.5, 5, and 10% respectively	liquid/oil/oil (L/O/O) phase separation	71.35%	0.74%	_	_	(Chen et al., 2019)

Figure 9. (a, b) The SEM micrographs of microspheres. (c) The size distribution of microspheres. (d) The concentration distribution of DOX in the left and median hepatic lobes of the rats during the experiment. (e) The plasma concentration of DOX in rats after injection of the drug (DOX) – loaded microsphere and free DOX during the experiment. Adapted with permission from Hsu et al. (2020). Copyright 2020, Elsevier.

Figure 10. The SEM micrographs of (a) porous PLGA microspheres loaded with doxorubicin and PEI25K/miR-519c (MP-4) and (b) the porous surface, and in-vitro cell viability evaluation of A549 cells treated with the release supernatants from different types of porous PLGA microparticles for 24 h (c) and 48 h (d). Adapted from with permission Wu et al. (2016). Copyright 2016, American Chemical Society.

Table 4. PLGA-based biodegradable microspheres for pulmonary drug delivery.

Drugs	PLGA composition	Preparation method	Particle size	Sustained drug release	Cell model	Animal model	References
Sophoridine	PLGA 50:50 (Mw: 20KDa)	O/O emulsification	17 μm	14 days	_	SD rats of male	(Wang et al., 2016)
Bisdemethoxycurcum	PLGA 50:50 (Mw: 50000)	O/W emulsification	8.5 μm	96 h	_	Sprague-Dawley rats	(Li et al., 2018)
Levofloxacin	RG 502H (PLGA 50:50, MW: 7000–17000, acid termi- nated) and RG 503 (PLGA 50:50, MW: 24,000–38,000, ethyl ester terminated)	W1/O/W2 emulsification	5 μm (MMAD of 7 μm)	_	Calu-3 cell line	_	(Gaspar et al., 2019)
Doxorubicin and miR-519c	PLGA-1.5A (50:50)	W1/O/W2 emulsification	42.7 − 47.6 μm	cumulative release values of doxorubicin and miR-519c were 80% and 50% respectively after 7 days	A549 cells	_	(Wu et al., 2016)
Budesonide	RG503H (PLGA 50:50, Mw: 28KDa)	Premix membrane O/W emulsification	3 μm	7 days	RAW264.7 cells and NR8383 cells	Male Sprague Dawley rats	(Li et al., 2019)
Gatifloxacin	PLGA 50:50 (RG502 and RG502H, Mw: 12KDa)	O/W emulsification	3–5 μm	cumulative release of 73–75% after 2 days	raw 264.7 mouse macrophage cell line	_	(Marcianes et al., 2019)

Table 5. PLGA-based biodegradable microspheres for ocular drug delivery.

Drugs	PLGA composition	Preparation method	Sustained drug release	Cell model	Animal model	References
Dexamethasone, melatonin, and coenzyme Q10	PLGA 50:50 (MW: 35,000 g/mol)	O/W emulsification	30 days	R28 cell line	Adult male Dark Agouti rats	(Arranz-Romera et al., 2019)
Dasatinib	Ratios and weight: PLGA 50:50, PLGA 65:35, and PLGA 75:25 (MW: 30–60, 50–80, and 65–120 KDa, respectively.) Concentration: 0.55–0.65 w/v% (PLGA in DCM)	Spray drying	Particle size >1.0 μm：55 days sub-micron: 15 days	Swine RPE cells	_	(Chauhan et al., 2019)
Tauroursodeoxycholic acid	PLGA 50:50	O/W emulsification	28 days with a cumulative release of 40.5%	_	Homozygous P23H line 3 albino rats	(Fernandez-Sanchez et al., 2017)
Dexamethasone	PLGA 50:50 (MW: 5 KDa)	Microfluidic technology	4 weeks with a cumulative release of 94.9%,	ARPE-19 cells	_	(Guo et al., 2018)

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