A combinational chemo-immune therapy using an enzyme-sensitive nanoplatform for dual-drug delivery to specific sites by cascade targeting

Abstract

Nanoparticle-based drug delivery faces challenges from the imprecise targeted delivery and the low bioavailability of drugs due to complex biological barriers. Here, we designed cascade-targeting, dual drug–loaded, core-shell nanoparticles (DLTPT) consisting of CD44-targeting hyaluronic acid shells decorated with doxorubicin (HA-DOX) and mitochondria-targeting triphenylphosphonium derivative nanoparticle cores loaded with lonidamine (LND) dimers (LTPT). DLTPT displayed prolonged blood circulation time and efficiently accumulated at the tumor site due to the tumor-homing effect and negatively charged hyaluronic acid. Subsequently, the HA-DOX shell was degraded by extracellular hyaluronidase, resulting in decreased particle size and negative-to-positive charge reversal, which would increase tumor penetration and internalization. The degradation of HA-DOX further accelerated the release of DOX and exposed the positively charged LTPT core for rapid endosomal escape and mitochondria-targeted delivery of LND. Notably, when DLTPT was used in combination with anti–PD-L1, the tumor growth was inhibited, which induced immune response against tumor metastasis.

Tumor‐Microenvironment‐Responsive Nanomedicine for Enhanced Cancer Immunotherapy

“…In combination with anti-PD-L1, the tumor growth was significantly hindered, leading to an intensive immune response against tumor metastasis (Figure 7j). [78] Apart from the MMP-2 and HAase, legumain that could hydrolyze asparagine in proteins and small molecule substrates was also overexpressed in a lot of cancers such as gastric cancer, ovarian cancer, and colorectal cancer. Taking advantage of this feature, our group fabricated legumain-responsive gold nanoparticles that were loaded with DOX and hydroxychloroquine (HCQ).…”

“…Reproduced with permission. [78] Copyright 2021, American Association for the Advancement of Science. p-Values: *p < 0.05; **p < 0.01; ***p < 0.001. f) The frequency of tumor-infiltrating CD4 + T cells, CD8 + T cells, and Tregs in mice with various treatments (n = 3, mean ± SD).…”

Smart Nanoparticles for Chemo-Based Combinational Therapy

“…For example, He et al fabricated multi-functional core-shell nanostructures with a HA-grafted shell, which was degraded at the tumor site by HAase and released loaded-DOX. Along with the degradation of the protecting shell, the lonidamine-loaded core was exposed for tumoral cells uptake [49]. This elaborated design allowed increased tumor penetration and internalization.…”

Emerging Nano-Based Strategies Against Drug Resistance in Tumor Chemotherapy

“…Like “Domino-effect”, the chemotherapy combined with immunotherapy could amplify the efficacy of anti-tumor treatment. Studies have demonstrated that many advanced nanoparticles are competent to break through barriers in combinatorial chemo-immune treatment ( Wei X. et al, 2019 ; He et al, 2021 ; Yan et al, 2021 ). Notably, the latest study reveals the phenomenon that some nanomaterials possess the inherent biological effect on immunotherapy.…”