Doxorubicin-Loaded PLGA Nanoparticles for Cancer Therapy: Molecular Weight Effect of PLGA in Doxorubicin Release for Controlling Immunogenic Cell Death

Abstract

Direct local delivery of immunogenic cell death (ICD) inducers to a tumor site is an attractive approach for leading ICD effectively, due to enabling the concentrated delivery of ICD inducers to the tumor site. Herein, we prepared doxorubicin (DOX)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) using different molecular weight PLGA (7000 g/mol and 12,000 g/mol), showing different drug release kinetics. The different release kinetics of DOX might differently stimulate a tumor cell-specific immune response by releasing damage-associated molecular patterns (DAMPs), resulting in showing a different antitumor response in the living body. DOX-PLGA7K NPs showed faster DOX release kinetics than DOX-PLGA12K NPs in the physiological condition. DOX-PLGA7K NPs and DOX-PLGA12K NPs were successfully taken up by the CT-26 tumor cells, subsequently showing different DOX localization times at the nucleus. Released DOX successfully lead to cytotoxicity and HMGB1 release in vitro. Although the DOX-PLGA7K NPs and DOX-PLGA12K NPs showed different sustained DOX release kinetics in vitro, tumor growth of the CT-26 tumor was similarly inhibited for 28 days post-direct tumor injection. Furthermore, the immunological memory effect was successfully established by the ICD-based tumor-specific immune responses, including DC maturation and tumor infiltration of cytotoxic T lymphocytes (CTLs). We expect that the controlled release of ICD-inducible chemotherapeutic agents, using different types of nanomedicines, can provide potential in precision cancer immunotherapy by controlling the tumor-specific immune responses, thus improving the therapeutic efficacy.

Current Strategies for Tumor Photodynamic Therapy Combined With Immunotherapy

“…In recent years, with the discovery of tumor immune checkpoint molecules, such as cytotoxic T lymphocyte (CTL)-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and its ligand PD-L1, important breakthroughs have been made in the study of antitumor immune mechanisms, and immunotherapy has become a promising tumor treatment (17,18). Currently, the main strategies in cancer immunotherapy include tumor vaccines, adoptive cellular immunotherapy (ACI), and immune checkpoint blockade (ICB) therapy (19)(20)(21). However, immune drugs alone are not effective for all patients.…”

PLGA Based Nanospheres as a Potent Macrophage-Specific Drug Delivery System

“…Pharmaceutics, regardless of their molar weight, can be loaded into PLGA drug delivery systems and consequently released from the matrix in a controlled manner. Consequently, a wide variety of active compounds can be used as payload of PLGA based drug delivery systems ranging from small molecules such as anti-tumour drugs with molar weight 0.5 kDa [ 15 ] to proteins and enzymes with molar mass up to 50 kDa [ 16 , 17 ]. The drug release profile of PLGA based drug delivery systems is usually characterized by the initial burst of a loaded drug followed by zero order kinetics release [ 18 ].…”

Notch Intracellular Domain Plasmid Delivery via Poly(Lactic-Co-Glycolic Acid) Nanoparticles to Upregulate Notch Pathway Molecules

“…Similarly, it has been shown that low molecular weight PLGA nanoparticles release the payload at a higher rate ( 76 – 78 ). Therefore, the molecular weight can influence how long a drug of interest is released and exposed to the area of interest ( 77 , 78 ). These previous studies support our data showing that the low molecular weight releases the payload after 5 days.…”

“…Even though the low molecular weight, 5-10 kDa, released the plasmid quickly, the nanoparticles were unstable in saline, a common liquid vehicle used for intravenous drug delivery (68,(72)(73)(74)(75). Similarly, it has been shown that low molecular weight PLGA nanoparticles release the payload at a higher rate (76)(77)(78). Therefore, the molecular weight can influence how long a drug of interest is released and exposed to the area of interest (77,78).…”