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This study aimed to evaluate the performance of cisplatin-loaded polymeric micelles (CDDP-PMs) with different drug/copolymer ratios of 1:1, 1:3 and 1:6 (w/w) prepared by coordinated complexation and self-assembly method. The mass ratio influenced the self-assembly behaviors and the complex degree, where both single- and double- complexation existed in CDDP-PMs. With the increase of CDDP/copolymer ratio, the particle size and drug loading increased, while encapsulation efficiency decreased. The PEG density of CDDP-PM1-6, CDDP-PM1-3 and CDDP-PM1-1 were 0.20, 0.61 and 0.38 PEG/nm2, respectively. CDDP-PM1-3 and CDDP-PM1-6 had similar sustained release behavior, while CDDP-PM1-1 showed burst release. Pharmacokinetics showed the AUC of CDDP-PM1-6, CDDP-PM1-3 and CDDP-PM1-1 was 27.2, 76.6 and 13.0 fold higher than CDDP solution. Tissue distribution presented the platinum concentration of CDDP-PM1-6, CDDP-PM1-3 and CDDP-PM1-1 was 1.03, 0.80 and 0.48 times of CDDP solution in kidney at 10 min, and 17.61, 28.63 and 16.6 times in tumor at 48 h respectively, indicating CDDP-PMs significantly reduced nephrotoxicity and increased tumor-targeting accumulation. In vivo antitumor test showed that CDDP-PMs exhibited an improved antitumor efficacy and lower systemic toxicity compared with CDDP solution. From CDDP-PM1-1 to CDDP-PM1-6, the toxicity decreased with the increase of copolymer ratio, but the tumor inhibition rate also decreased. CDDP-PM1-3 had relative high therapeutic effect and low toxicity compared with other formulations. CDDP-PM1-3 could improve the antitumor efficacy by increasing the dose within systemic tolerability, but CDDP solution cannot. This work provides an effective strategy by modulating drug/copolymer ratio of CDDP-PMs to balance the antitumor efficacy and toxicity for better payoff. Statement of Significance Cancer chemotherapy always exists a contradiction between antitumor efficacy and toxicity. Higher efficacy against tumor often associated with larger toxicity for normal tissues. This work provides an important strategy by modulating the drug/copolymer ratios to balance the antitumor efficacy and toxicity to obtain better payoff. The cisplatin-loaded polymeric micelles (CDDP-PMs) based on the complexation between CDDP and copolymer with different mass ratios make differences in vitro and in vivo because of the single- or double-complexation degree. Most importantly, we found the balance at CDDP/copolymer ratio of 1:3, which has relative high therapeutic effect and low toxicity compared with other formulations. CDDP-PM1-3 could improve the antitumor efficacy by increasing the dose within systemic tolerability, but CDDP solution cannot.

Chemotherapy is an effective anti-tumor treatment. Some anticancer chemotherapeutic drugs can not only induce cell death, but can also elicit antitumor immune responses. Here, the stability of cisplatin-loaded polymeric micelles (CDDP-PMs), pharmacokinetic drug-drug interactions of CDDP and anti-PD-L1 antibody (aPD-L1) in vivo and the alteration of the tumor microenvironment by combination of CDDP-PMs and aPD-L1 were evaluated. CDDP-PMs were fabricated by coordinated complexation and self-assembly method for tumor targeting. CDDP-PMs with higher mass ratio of copolymer have higher thermodynamic stability. The pharmacokinetic study showed that the CDDP and aPD-L1 were metabolized and cleared by two different pathways, suggesting that there is almost no risk of potential drug interactions between CDDP and aPD-L1 and the combination of aPD-L1 and CDDP- PMs may not alter the tissue distribution of CDDP. In vivo antitumor test showed that the tumor growth inhibition rates of CDDP-PMs combined with medium-dose aPD-L1 and CDDP-PMs combined with high-dose PD-L1 were 89.41% and 93.16%, respectively and therapeutic efficacy can be further increased by increasing the dose of aPD-L1 in co-administration group. This therapeutic system by combining chemotherapy and immunotherapy further increases the link between them and holds great potential to offer better safety and antitumor efficacy profiles.

Platinum chemotherapy is widely used in first-line treatment of patients with various cancers. PD-1/PD-L1 inhibitors have shown efficacy in several cancers, and the combination of platinum-based chemotherapy and PD-1/PD-L1 inhibitors has gradually become the focus of attention. Recently, the combination therapy has exhibited significant effects in preclinical models and clinical trials.This review summarizes preclinical and clinical studies of the combination therapy in various cancers, and further explores mechanisms of the treatment. Furthermore, exploration of the mechanism demonstrates that the combination therapy plays a combination role in two ways. On the one hand, the positive effects of platinum-based chemotherapy on immunomodulation can be harnessed to increase the sensitivity of tumor cells to PD-1/PD-L1 inhibitors. On the other hand, platinum-based chemotherapy may upregulate PD-L1 expression in tumor tissue and exert a negative immunomodulatory effect, which can be counteracted by PD-1/PD-L1 inhibitors through their action pathway. What's more, different types of platinum-based chemotherapy exert different immunomodulation properties.This review describes a potential for the combination of PD-1/PD-L1 inhibitors and novel nanoparticles composed of platinum-loaded complex to yield positive effects in a wide range of doses, thus achieving higher therapeutic effects and lower side effects.Treg: regulatory T cell; MDSC: myeloid-derived suppressor cell; TAM: tumor-associated macrophage; IL: interleukin; PD-1: programmed cell death protein-1; PD-L1: programmed death-ligand-1; NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer; HNSCC: head and neck squamous cell cancer; ICD: immunogenic cell death; TME: tumor microenvironment; CTLs: cytotoxic T lymphocytes; TCR: T cell receptor; MHC class 1: major histocompatibility complex class 1; DC: dendritic cell; APC: antigen-presenting cell; PD-L2: programmed death-ligand-2; STAT6: signal transducers and activators of transcription 6; PLG: poly (L-glutamic acid); mPEG: methoxy poly (ethylene glycol); LLC1: Lewis lung carcinoma 1; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; MOC1: mouse oral cancer 1; cGAS: cyclic guanosine monophosphate-adenosine monophosphate synthase; STING: stimulator of interferon genes; FDA: food and drug administration; cHL: classical Hodgkin's lymphoma; PMBCL: primary mediastinal large B-cell lymphoma; HCC: hepatocellular carcinoma; MCC: merkel cell carcinoma; RCC: renal cell carcinoma; ORR: overall response rate; OR: overall response; OS: overall survival; PFS: progression-free survival; vs: versus; EFGR: epidermal growth factor receptor; ALK: anaplastic lymphoma kinase; ES: extensive stage; CPS: combined positive score; DOR: duration of response; ITT: intention to treat; NMPA: national medical products administration; TKI: tyrosine kinase inhibitor; NPC: nasopharyngeal cancer; DLT: dose-limiting toxicity; MTD: maximum tolerated dose; TNBC: triple-negative breast cancer; GC: gastric cancer; GEJC: gastroesophageal junction carcinoma; DCR: disease control rate; BTC: biliary tract cancer; TTR: time to response; PR: partial response; SD: stable disease; PD: progressive disease; IC