Delivery of doxorubicin and paclitaxel from double-layered microparticles: The effects of layer thickness and dual-drug vs. single-drug loading.
Double-layered microparticles composed of poly(d,l-lactic-co-glycolic acid, 50:50) (PLGA) and poly(l-lactic acid) (PLLA) were loaded with doxorubicin HCl (DOX) and paclitaxel (PCTX) through a solvent evaporation technique. DOX was localized in the PLGA shell, while PCTX was localized in the PLLA core. The aim of this study was to investigate how altering layer thickness of dual-drug, double-layered microparticles can influence drug release kinetics and their antitumor capabilities, and against single-drug microparticles. PCTX-loaded double-layered microparticles with denser shells retarded the initial release of PCTX, as compared with dual-drug-loaded microparticles. The DOX release from both DOX-loaded and dual-drug-loaded microparticles were observed to be similar with an initial burst. Through specific tailoring of layer thicknesses, a suppressed initial burst of DOX and a sustained co-delivery of two drugs can be achieved over 2months. Viability studies using spheroids of MCF-7 cells showed that controlled co-delivery of PCTX and DOX from dual-drug-loaded double-layered microparticles were better in reducing spheroid growth rate. This study provides mechanistic insights into how by tuning the layer thickness of double-layered microparticles the release kinetics of two drugs can be controlled, and how co-delivery can potentially achieve better anticancer effects.


CONCLUSIONS
While the release of multiple drugs has been reported to achieve successful apoptosis and minimize drug resistance, most conventional particulate systems can only deliver a single drug at a time. Recently, although a number of formulations (e.g. micellar nanoparticles, liposomes) have been successful in delivering two or more anticancer agents, sustained co-delivery of these agents remains inadequate due to the complex agent loading processes and rapid release of hydrophilic agents. Therefore, the present work reports the multilayered particulate system that simultaneously hosts different drugs, while being able to tune their individual release over months. We believe that our findings would be of interest to the readers of Acta Biomaterialia because the proposed system could open a new avenue on how two drugs can be released, through rate-controlling carriers, for combination chemotherapy.
School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore.
Wei Li
WL
Lee
Molecular Engineering Laboratory, A(∗)STAR, Proteos #03-13, 61 Biopolis Drive, Singapore 138673, Singapore.
Wei Mei
WM
Guo
Molecular Engineering Laboratory, A(∗)STAR, Proteos #03-13, 61 Biopolis Drive, Singapore 138673, Singapore.
Vincent H B
VHB
Ho
School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore.
Amitaksha
A
Saha
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
Han Chung
HC
Chong
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore; Institute of Molecular and Cell Biology, A(∗)STAR, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
Nguan Soon
NS
Tan
Department of General Surgery, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore.
Ern Yu
EY
Tan
School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore; Singapore Centre on Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University, Singapore 637551, Singapore. Electronic address: joachimloo@ntu.edu.sg.
Say Chye Joachim
SCJ
Loo
D065966:Absorption, Physicochemical; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000737:chemistry*; D002214:Capsules / Q000008:administration & dosage / Q000138:chemical synthesis*; D002470:Cell Survival / Q000187:drug effects*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry*; D004058:Diffusion; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry*; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D061986:MCF-7 Cells; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry*; D011091:Polyesters; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry
D002214:Capsules; D003692:Delayed-Action Preparations; D011091:Polyesters; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C033616:poly(lactide); D004317:Doxorubicin; D017239:Paclitaxel
Biodegradable polymer; Chemotherapy; Drug delivery; Microparticles; Multicellular spheroids