Light-assisted hierarchical intratumoral penetration and programmed antitumor therapy based on tumor microenvironment (TME)-amendatory and self-adaptive polymeric nanoclusters
Graphical abstract
Introduction
Nanomedicine has been extensively engineered to target, diagnose tumors precisely, and ultimately, enhance the efficacy of tumor eradication [[1], [2], [3], [4], [5]]. Systemically administered nanomedicine is expected to accumulate in the solid tumors via the enhanced permeability and retention (EPR) effect [6,7], induced by the leaky vasculature and defective lymphatic drainage of tumors. However, this passive targeting leads to the unsatisfactory heterogeneous distribution of nanomedicine at perivascular sites [8]. Moreover, the tightly packed tumor cells within solid tumors and extracellular matrix (ECM) abysmally prevent nanomedicine from penetrating into the deeper regions of tumor tissues [9]. To enable stronger anti-cancer efficacy, there is a dire need for new strategies to overcome the anatomical and physiological barriers and to enable deep intratumoral penetration of nanomedicine.
Recently, various strategies have been reported to enhance the tumor penetration of nanomedicine by tailoring the nano-properties [10] and/or regulating the tumor microenvironment (TME) [[11], [12], [13]]. Physicochemical characteristics (e.g., particle size [14,15], surface charge [16], and shape [17]) of nanoparticles (NPs) greatly influence their intratumoral penetration [18]. Smaller and positively charged NPs are prone to penetrate into deeper layers of solid tumors [[19], [20], [21]], while such tiny and cationic NPs are readily to be cleared from blood vessels [22]. Thus, NPs that are capable of size shrinkage in response to either endogenous [23,24] or external [25] stimuli represent one of the most promising approaches with encouraging success. To this end, size-shrinkage strategies such as peeling onions [26], surface-carrying [21], trojan horse [27,28], and pandora box [29] have been developed. On the other hand, the pharmacological modulation of TME has also been used to promote the deep intratumoral penetration of nanomedicine [30,31]. For instance, enzymes (such as collagenase [32,33] and hyaluronidase [34]) or small molecules (such as losartan [35,36]) have been used to degrade the ECM of tumors. In addition, normalization of tumor vasculature [37], tumor vascular disruption by Combretastatin A-4 Phosphate (CA4P) [38], and stromal cell depletion [39] have also been demonstrated to enhance the permeability of tumors. Nevertheless, these stimuli-responsive nanosystems often suffer from inadequate sensitivity and selectivity toward endogenous stimuli in tumors, lacking precise control over the nano-property transformation. The existing TME priming technologies may lead to non-specific adverse effects and limited tumor eradication efficiency. For instance, enzymes and losartan inevitably produce non-specific toxicity when eradicating ECM components. Tumor vasculature normalization may compromise the EPR effect, reducing the tumor accumulation of nanomedicine [40]. Additionally, limited outcomes are often achieved with a single strategy to promote intratumoral penetration. Therefore, novel strategies are still highly demanded to bypass the intercellular barriers in tumors and concurrently mediate self-adaption in terms of the nano-properties, thus cooperatively maximizing the tumor penetration and therapeutic efficacy of nanomedicine in a spatiotemporally and hierarchically controlled manner. Light as a non-invasive and external stimulus represents an ideal tool for modifying the TME and transforming the nano-properties, because it features easy maneuverability, high spatiotemporal precision, and minimal damage to normal tissues within the safe optical power range [[41], [42], [43]]. However, such a light-assisted strategy capable of TME priming and nano-transformation is still highly lacking.
Cancer-associated fibroblasts (CAFs) are mesenchymal-like cells that constitute the major population of tumor stroma and they play crucial roles in tumor transformation, proliferation, and invasion [44,45]. Once perpetually activated, CAFs will neither restore normal phenotype nor undergo apoptosis and elimination. CAFs regulate the dynamic and reciprocal interactions among the malignant epithelial cells, the ECM, and the numerous non-cancerous cells in tumors [13]. Also, they can alter composition and physicochemical properties of ECM, inducing tumor fibrosis [46]. Notably, fibroblast activation protein-α (FAP-α), a type II transmembrane cell surface protein, is highly and specifically expressed by CAFs, and it has been found in more than 90% of human epithelial tumors yet with minimal expression in normal cells [[47], [48], [49], [50]]. In the TME, FAP-α-positive CAFs are distributed mainly surrounding the tumor-derived vascular endothelial cells, limiting the efficient penetration of nanomedicine into deeper tumor regions. Therefore, therapeutic strategies specifically targeting the CAFs within the tumor stroma hold great potentials toward the enhancement of tumor penetration.
Based on these understandings, we herein developed the TME-amendatory and self-adaptive nanoclusters (NCs) capable of light-assisted CAF depletion and size/charge conversion, which spatiotemporally and hierarchically promoted tumor penetration to strengthen the anticancer potency in CAF-rich tumors. Particularly, small-sized, positively charged polyamidoamine (PAMAM) dendrimer (~5 nm) conjugated with chlorin e6 (Ce6) and loaded with DOX (DC/D) was encapsulated into large-sized NCs (~50 nm) self-assembled from FAP-α-targeting peptide-modified, singlet oxygen (1O2)-sensitive (SOS), main-chain degradable polymers via the double emulsion method. The NCs could target the CAFs in the tumor stroma after systemic administration, and the tumor-site light irradiation generated high levels of 1O2 to degrade the shell of NCs and concurrently deplete the CAFs. The dense tumor stroma was thus attenuated, and the small-sized, positively charged DC/D released from the NCs could efficiently penetrate into deeper regions of tumors by taking advantage of their small size, positive surface charge, and the light-assisted stroma depletion. Finally, the released DOX from DC/D together with the 1O2 produced by DC/D under light irradiation synergistically eradicated the tumor cells imbedded deep in the solid tumors (Fig. 1).
Section snippets
Materials
PAMAM (G3) dendrimer was purchased from Chenyuan Molecular New Material Co., LTD. (Weihai, China). Poly(ethylene glycol) monomethyl ether (mPEG, molecular weight (MW) = 5 kDa), dibutyltin dilaurate (DBTDL), chlorin e6 (Ce6), 1-ethyl-3-(3-dimethyllaminopropyl) carbodiimide (EDC), maleimide PEG (Mal-PEG, MW = 7.5 kDa), and 1-hydroxybenzotriazole (HoBt) were purchased from J&K Scientific Co., Ltd. (Beijing, China). 4-Dimethylaminopyridine (DMAP), lysine diisocyanate (LDI), and 1,8-octylene glycol
Synthesis and characterization of block polymers
mPEG-(1O2)PU-mPEG, an SOS and main-chain degradable triblock polymer, was synthesized via polycondensation between EDSE and LDI to form the inner PU block and subsequent termini-capping with two mPEG blocks (Scheme S1) [54]. The maleimide-terminated PEG-(1O2)PU-PEG (Mal-PEG-(1O2)PU-PEG-Mal) and the 1O2 non-sensitive triblock polymers (mPEG-PU-mPEG and Mal-PEG-PU-PEG-Mal) were similarly prepared (Scheme S1). The chemical structures of EDSE and block polymers were confirmed by their corresponding
Conclusion
In summary, TME-amendable and self-adaptive NCs were developed to mediate hierarchical intratumoral penetration and programmed antitumor therapy via light-assisted CAFs depletion, size shrinkage, and charge conversion. Targeting of the NCs to CAFs followed by light irradiation generated lethal levels of 1O2 to kill CAFs and attenuate the tumor stroma, which in the meantime, destroyed the 1O2-dissociable NCs to release the encapsulated, small-sized and positively charged DC/D. The effective CAF
CRediT authorship contribution statement
Jing Yan: Conceptualization, Methodology, Investigation, Software, Writing - original draft. Qinghua Wu: Formal analysis, Validation. Ziyin Zhao: Investigation, Data curation. Jianhua Wu: Formal analysis. Huan Ye: Resources, Software. Qiujun Liang: Visualization, Investigation. Zhuchao Zhou: Supervision, Resources, Writing - review & editing. Mengying Hou: Validation. Xudong Li: Visualization. Yong Liu: Supervision, Writing - review & editing. Lichen Yin: Conceptualization, Supervision, Funding
Acknowledgements
We acknowledge the financial support from the National Natural Science Foundation of China (51873142 and 51722305), the Ministry of Science and Technology of China (2016YFA0201200), 111 project, and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). We thank Professor Yongbing Chen at the Second Affiliated Hospital of Soochow University for providing patient-derived CAFs.
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