In Vivo Environment‐Adaptive Nanocomplex with Tumor Cell–Specific Cytotoxicity Enhances T Cells Infiltration and Improves Cancer Therapy

Abstract

Drug delivery strategies possessing selectivity for cancer cells are eagerly needed in therapy of metastatic breast cancer. In this study, the chemotherapeutic agent, docetaxel (DTX), is conjugated onto heparan sulfate (HS). Aspirin (ASP), which has the activity of anti-metastasis and enhancing T cells infiltration in tumors, is encapsulated into the HS-DTX micelle. Then the cationic polyethyleneimine (PEI)-polyethylene glycol (PEG) copolymer binds to HS via electrostatic force, forming the ASP-loaded HS-DTX micelle (AHD)/PEI-PEG nanocomplex (PAHD). PAHD displays long circulation behavior in blood due to the PEG shell. Under the tumor microenvironment with weakly acidic pH, PEI-PEG separates from AHD, and the free cationic PEI-PEG facilitates the cellular uptake of AHD by increasing permeability of cell membranes. Then the overexpressed heparanase degrades HS, releasing ASP and DTX. PAHD shows specific toxicity toward tumor cells but not normal cells, with advanced activity of inhibiting tumor growth and lung metastasis in 4T1 tumor-bearing mice. The number of CD8 + T cells in tumor tissues is also increased. Therefore, PAHD can become an efficient drug delivery system for breast cancer treatment.

Developing New Cancer Nanomedicines by Repurposing Old Drugs

“…As atypical paradigm, Li et al have established acomposite nanosystem for cancer treatment by co-loading the chemotherapeutic agent docetaxel (DTX) and aspirin in micelles (Figure 7). [55] Theh eparanase overexpressed in cancer cells can degrade the heparan sulfate of micelles to…”

“…Phase I/II virus infection alycolysis inhibition for reduction of energy production [10,18] disulfiram approved alcohol abuse chelating with Cu 2+ to generate toxic CuET [26,29] artemisinin approved malaria reacting with Fe 3+ to generate toxic free radicals [35] chloroquine approved malaria autophagy blockage for inhibiting self-detoxication [42] metformin approved Type II diabetes OXPHOS inhibition to modulate hypoxia and lower energy production [50] aspirin approved pain, fever, and inflammation cyclooxygenase inhibition for enhancing Tcell infiltration [55] Angewandte Chemie…”

“…have established a composite nanosystem for cancer treatment by co‐loading the chemotherapeutic agent docetaxel (DTX) and aspirin in micelles (Figure 7). [55] The heparanase overexpressed in cancer cells can degrade the heparan sulfate of micelles to favor the release of aspirin and DTX, triggering a cancer‐specific therapeutic effect. The number of CD8 + T cells was increased in tumor tissues owing to the immunoregulatory function of aspirin.…”

Developing New Cancer Nanomedicines by Repurposing Old Drugs

“…Phase I/II virus infection alycolysis inhibition for reduction of energy production [10,18] disulfiram approved alcohol abuse chelating with Cu 2+ to generate toxic CuET [26,29] artemisinin approved malaria reacting with Fe 3+ to generate toxic free radicals [35] chloroquine approved malaria autophagy blockage for inhibiting self-detoxication [42] metformin approved Type II diabetes OXPHOS inhibition to modulate hypoxia and lower energy production [50] aspirin approved pain, fever, and inflammation cyclooxygenase inhibition for enhancing Tcell infiltration [55] Angewandte Chemie Kurzaufsätze 22020 www.angewandte.de…”

“…As atypical paradigm, Li et al have established acomposite nanosystem for cancer treatment by co-loading the chemotherapeutic agent docetaxel (DTX) and aspirin in micelles (Figure 7). [55] Theh eparanase overexpressed in cancer cells can degrade the heparan sulfate of micelles to favor the release of aspirin and DTX, triggering ac ancerspecific therapeutic effect. Then umber of CD8 + Tc ells was increased in tumor tissues owing to the immunoregulatory function of aspirin.…”