Role of Polymeric Local Drug Delivery in Multimodal Treatment of Malignant Glioma: A Review

Figures & data

Figure 1 Illustrations of challenges in treating malignant glioma.

Figure 2 Gross appearances and microscopic images of postimplantation parenchyma. The number in the lower left corner of each image indicates the number of weeks following the implantation of nanofibrous membranes (NMs) or microparticles. (A) Implanted PLGA NMs degraded without causing the accumulation of transudate and exudate fluids. (B) Injected microparticles were initially dense and large (indicated by black arrows); few dense areas were observed at the end of the study. (C) Pathological examination (H&E stain) indicated no leukocyte accumulation after implantation with NMs. The number in the lower-right corner of each image indicates cell numbers (mm²). Progressively decreased cellularity was noted after chemotherapy agent loaded NMs implantation. (D) Injected microparticles (indicated by black arrows) degraded progressively and the presence of temporal inflammation reaction (accumulation of numerous inflamed leukocytes, indicated by small arrows). Magnification: 100×.

Figure 3 (A) Local delivery system that bypasses the blood–brain barrier (BBB) to reach the brain tumor. (B) NPs crossing the BBB with the aid of FUS and an external magnetic field.

Table 1 Summary of Polymeric Vehicles for Local Delivery with Therapeutic Potential in MG Treatment

Single Agent
Therapeutical Agent	Type of Polymer	Structure of Polymeric Vehicle	In vivo/in vitro Model	Treatment Outcome		Ref.
SN-38	PLGA	MP	Orthotopic glioma rats (F98)	Significant therapeutic efficacy		[^Citation33]
SN-38	NK-012	Micelle	Orthotopic GS rats and GBM mice (9L, U87)	Excellent efficacy		[^Citation68]
SN-38	PLEC	Depot	Orthotopic GBM mice (U87)	Better antitumor efficacy and reduced toxicity		[^Citation69]
SN-38	PCL/GT	Nanofiber	In vitro U251/ U87 cell	Good anti-tumor function in vitro		[^Citation70]
BCNU	Poly-CPP-SA	Disc	Orthotopic GS rats (9L)	Effective antitumor efficacy and prolong survival rate		[^Citation64]
BCNU	PEG-PLA	Ultrafine fiber	In vitro, C6 glioma cell,	Not affect the growth of C6 glioma cell		[^Citation58]
BCNU	PLGA	Wafer	9L GS, subcutaneous	Delayed tumor growth		[^Citation62]
BCNU	PLGA	Wafer	In vitro, XF-498 cell	Increase antitumor activity		[^Citation63]
BCNU	PLGA	Nanofiber	In vivo, concentration	Sustained release high concentration > 8 week		[^Citation39]
BCNU	Shell: panH Core: Fe3O	Core-shell magnetic NP	In vivo, concentration	Increase the concentration and retention		[^Citation119,^Citation137]
Rapamycin	Caprolactone-glycolide (35:65)	Beads	Orthotopic GS rats (9L)	Significant increase in survival		[^Citation65]
Doxorubicin	Polysorbate	Polysorbate-coating NP	Orthotopic glioma rats (101/8)	Considerable antitumor effect		[^Citation138]
Doxorubicin	PLGA	NP	Orthotopic glioma rats (101/8)	Considerable anti-tumor effect		[^Citation139]
5-FU	PLGA	Wafer	Orthotopic glioma rats (C6)	Drug diffusion is limited to the implantation site.		[^Citation140]
5-FU	PLGA	Microspheres	Orthotopic glioma rats (C6)	Decrease mortality		[^Citation141]
Bucladesine	PLGA	Pellets	Clinical GBM patient	Delay of recurrence		[^Citation142]
n-butyliden-ephthalide	Polyanhydride	Wafer	In Vitro GBM cell line	Increased the survival rate and inhibited tumor invasion.		[^Citation28]
TMZ	MPC	Nanostructures from the block	Orthotopic GBM mice (U87 and T98)	2- to 19-retention times longer than that of free TMZ.		[^Citation143]
Idarubicin	PLGA, PGACL	Wafer	In vitro (U87MG cell line).	High inhibition of proliferation		[^Citation144]
Paclitaxel	PLGA, PEG	NP	Orthotopic GS rats (9L)	Delayed tumor growth and enhance drug distribution		[^Citation145]
Camptothecin	EVAc	Particles	Orthotopic GS rats (9L)	Significantly extended survival		[^Citation66]
Doxorubicine	PLA, BEP	Patch	Orthotopic U87-MG canine	Suppressed tumor volume and enhanced survival rate		[^Citation146]
Multiple Agents
Concurrent Different Chemotherapy Agents
Therapeutical Agent	Type of Polymer	Structure of Polymeric Vehicle	In vivo/in vitro Model	Treatment Outcome		Ref.
BCNU, Cisplatin, Irinotecan	PLGA	Nanofiber	Orthotopic glioma rats (C6)	Prolong survival and reduced the malignancy		[^Citation42,^Citation43]
Emozolomide, Etoposide	PLGA/PEG	MP/ paste	Orthotopic GS rats (9L)	Significant overall survival benefit		[^Citation44]
Combined Other Biotherapeutic Agent
Therapeutic Agent	Biotherapeutic Agent	Type of Polymer	Structure of Polymeric Vehicle	In vivo/in vitro Model	Treatment Outcome	Ref.
BCNU, Cisplatin, Irinotecan	Antiangiogenic (Combretastatin)	PLGA	Bi-layered NM	Orthotopic GS, glioma rats (9L, F98)	Prolong survival and reduced tumor progression and malignancy	[^Citation46,^Citation86]
BCNU, TMZ	O^6-BG	PLGA	Hybride -structured NM	Orthotopic glioma rats (9L, F98)	Prolong survival and reduced tumor progress and malignancy	[^Citation35,^Citation36]
Irinotecan	Metformin	PLGA	NP	In vitro GBM cell (U-87) and Orthotopic GBM mice (U87)	Significantly reduced the volume of extracted cancer	[^Citation90]
None	T-lymphocyte-associated antigen 4 (a-CTLA-4) and programmed cell death-1 (a-PD-1)	Poly(β-L-malic acid)	NP	Orthotopic GBM mice (GL261)	Effective GBM treatment via activating immune response.	[^Citation47]
None	Several anti-GBM genes (Robo1, YAP1, NKCC1, EGFR, and survivin)	PBAE	NP	Orthotopic mice model of human GBM cell	Leads to high GBM cell death, reduces GBM migration	[^Citation48]
None	siRNA, linear DNA, and circular DNAs	PBAE	NP	In vitro, GBM 319 cells	Increase delivery of both DNA and siRNA	[^Citation147]
None	Binimetinib	Poly(butadiene-b-ethylene oxide)	Polymersomes	In vitro BBB model	Cross the in vitro BBB model	[^Citation148]
None	siRNA	Chitosan	NP	Orthotopic mice model (GL261)	Targeting Gal-1 gene, effective treatment of GBM	[^Citation149,^Citation150]
None	Curcumin	PLGA Chitosan	NP	RG2 rat glioma model	Tumor size decreased significantly	[^Citation91]
Paclitaxel	Curcumin	PLGA	MNP	Orthotopic mice model (U87)	Prolong survival and reduced tumor size	[^Citation121]

Abbreviations: GBM, glioblastoma multiforme; GS, gliosarcoma; PLGA, poly(L-lactide-co-glycolide); PGACL, poly(glycolide-co-ε-caprolactone); PBAE, poly(beta-amino ester); PEG-PLA, poly(ethylene glycol)-poly(L-lactic acid); MPC, 2-methacryloyloxyethyl phosphorylcholine; EVAc, ethylene-vinyl acetate co-polymer; MP, microparticle; NM, nanofibrous membrane; NP, nanoparticle; BEP, biodegradable electronic patch.

Figure 4 (A) Sustained release of a single chemotherapy agent (BCNU) from 50:50 PLGA nanofibrous membranes (NMs). (B) Sequential release of three chemotherapy agents (BCNU, irinotecan, and cisplatin) from 50:50 PLGA NMs followed by release of an antiangiogenetic agent (combrastatin) 75:25 PLGA NMs. (C) Sequential release of O⁶-BG from 50:50 PLGA NMs followed by release of two alkylating agents (BCNU and TMZ) from 75:25 PLGA NMs. (D) Contribution of NMs of different designs to antiglioma efficacy in an orthotopic animal model.

Table 2 Comparison of Advanced Local Delivery with Systemic Delivery Methods for Treating MG

	Advanced Local Delivery	Nanoparticle	Surface-Decorated Nanoparticle	Magnetic Assisted Nanoparticle	Focused Ultrasound
Mechanism	Bypassing BBB	Open BBB	Open BBB Increase retention	Increase retention of MNPs	Increase permeability of BBB
Transport	Direct release of agents into tumor site	Through BBB	Open BBB	Tumor vascularity change → allow NP cross BBB	Transient disruption of BBB
Administration route	After tumor resection Intratumoral injection*	Intravascular CED*	Intravascular CED*	Intravascular CED*	Intravascular CED*
Systemic toxicity/ side effect	Less	As systemic administration	As systemic administration	As systemic administration	As systemic administration
Efficacy	100	0.5–4.3%	0.8–21.2% (1.91–4.93 fold higher than NP)	3.6–12 fold higher than NP	2–10 fold retention than NP
Limitation	Short diffuse distance	Small size (15–20 nm) is preferred	Small size (15–20 nm) is preferred	Large nanoparticles (>100 nm) may be difficult to target MGs	Need image guided Small size (15–20 nm) is preferred

Note: *Need minimal operation- burr hole.

Abbreviations: MNP, magnetic nanoparticles; CED, convection-enhanced delivery.

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