Table 4.

Summary of studies evaluating novel drug delivery systems for optimized intraperitoneal chemotherapy in CPM.

Author, year, country	n	Study subjects	Objective(s)	Delivery technique	Therapeutic response	Survival/viability	Toxicity	Other
Harrison et al., 2007 [72]	29	Human study	To examine the safety and pharmacokinetics of intraperitoneal pegylated liposomal doxorubicin (PLD) used in the context of HIPEC in patients with advanced abdominal-only malignancies	Nanoliposomes		MOS 30.6 months	Grade 3 to 4 complications: 9/29	Increased systemic doxorubicin levels found with use of nanoliposomes up to 24 hrs postperfusion
Lin et al., 2009, China [71]	6	Mouse model	To evaluate the biodistribution and pharmacokinetics of 111In-labeled vinorelbine- (VNB-) encapsulated PEGylated liposomes (IVNBPL) after intraperitoneal and intravenous administration	Nanoliposomes	Enhanced drug concentration and penetration into peritoneal surface noted with use of 111In-labeled VNB-PEGylated liposomes
Keese et al., 2009, Germany [53]	16	Mouse model	To compare the therapeutic efficacy of either mitoxantrone and doxorubicin delivered in standard free form with drug delivery using drug eluting beads	Drug-eluting beads	Similar decline in tumour load and tumour volume Increased toxicity with free drug delivery	The authors concluded that bead encapsulation of chemotherapeutic drugs may show the advantage of less toxicity in peritoneal spread of colorectal cancer
Serafino et al., 2011, Italy [61]	12	Rat model	To provide in vitro and in vivo preclinical data on the antitumour efficacy of ONCOFID™-S, a novel bioconjugate of hyaluronic acid (HA) with SN-38 (the active metabolite of irinotecan)	HA bioconjugate	Significantly decreased ascites and tumour volume with bioconjugation vs. control and vs. free drug (p < 0.0001 and p < 0.005)		HA-SN38 bioconjugation resulted in equivalent cytotoxicity but 16-fold increase in antiproliferative activity compared to free drug	HA-SN38 bioconjugation demonstrated ability to block cell cycle at G2 in lower concentrations than with free drug Increased tumour cell uptake of HA-linked drug was noted via CD44, which is overexpressed in a wide variety of cancer subtypes including colorectal
Colson et al., 2011, USA [43]	12	Mouse model	To assess the antitumour efficacy of paclitaxel-loaded pH-responsive expansile nanoparticles (Pax-Enp) in vitro and using an in vivo mouse model of peritoneal carcinomatosis	Nanoparticles	Pax-Enp led to a significantly enhanced reduction in tumour volume compared with free drug	Median survival: Pax-Enp: 54 days Free drug: 29 days
Tsai et al., 2011, China [70]	10	Mouse model	To evaluate the biodistribution, pharmacokinetics, micro-SPECT/CT image, dosimetry, and therapeutic efficacy of 188Re-labeled nanoliposomes	Nanoliposomes	Radiotherapeutics with 188Re liposomes led to enhanced inhibition of tumour growth and ascites compared with 5-FU p < 0.05	Radiotherapeutics with 188Re liposomes increased survival by 34.6% compared with 5-FU alone (p < 0.05)
Gong et al., 2012, China [50]	12	Mouse model	To develop a dual drug delivery system of self-assembled micelles in a thermosensitive hydrogel composite to deliver hydrophilic and hydrophobic drugs, simultaneously	Micelles and hydrogels	Dual delivery system comprised of pacitaxel-5FU hydrogel decreased tumour weight more than conventional monotherapeutic drug delivery	Survival: Pacitaxel-5FU 42 days Free drug 35 days (p < 0.05)	In vivo experiments in a mouse model showed the dual drug delivery system to be nontoxic and biocompatible	Dual drug delivery system led to enhanced bioavailability (18.7x greater for pacitaxel and 21.6x for 5-FU) compared with conventional delivery
Liu et al., 2013, China [69]	6	Mouse model	To develop a biodegradable and injectable composite drug delivery system using camptothecin- (CPT-) loaded polymeric microspheres (MS) in thermosensitive hydrogel for CPM therapy	Microspheres and hydrogels	Significant reduction in mean number and weight of tumour nodules post therapy with microsphere+hydrogel group: CPT-MS/hydrogel group (19.17 ± 9.64; 0.59 ± 0.20 g) CPT-MS (56.83 ± 14.58, p < 0.001; 1.30 ± 0.17 g, p < 0.001) Free CPT (93.67 ± 12.96, p < 0.001; 2.10 ± 0.17 g, p < 0.001) Blank MS/hydrogel (154.67 ± 19.13, p < 0.001; 3.33 ± 0.29 g, p < 0.001)
Wu et al., 2014, China [63]	12	Zebrafish and mouse models	To investigate whether counteracting the hydrophobicity of chetomin through encapsulation into polymeric micelles (Che-M) could provide a means of enhancing therapeutic efficacy in CPM compared to chetomin in standard form (Che)	Micelles	Tumour volume, length, vessel branching lower in CheM vs. Che (p < 0.01)			% of tumour cells undergoing apoptosis following therapy: Che-M—7.12%, Che—5.75% (p < 0.05)
Fan et al., 2014, China [47]	32	Mouse model	Docetaxel-loaded porous microspheres (DOC-MS) vs. free docetaxel (DOC)	Microspheres		Median survival: DOC-MS 33 day; DOC-29 days (p < 0.05)
Montagner et al., 2014, Italy [56]	6	Mouse model	To assess the therapeutic efficacy of two bioconjugates derived from the chemical linking of paclitaxel or SN-38 (the active metabolite of irinotecan), to HA in a mouse model of CPM	HA bioconjugates	(i) In vivo, efficacy of bioconjugates or free drugs against luciferase-transduced tumour cells was assessed by bioluminescence optical imaging and by recording mouse survival. The intraperitoneal administration of bioconjugates in tumour-bearing mice led to improved therapeutic efficacy compared with unconjugated drugs (ii) In vitro, bioconjugates were selectively internalized through mechanisms largely dependent on interaction with the CD44 receptor and caveolin-mediated endocytosis, which led to accumulation of compounds into tumour cell lysosomes
Fan et al., 2015, China [48]	12	Mouse model	To compare the efficacy of intraperitoneal docetaxel-loaded hydrogel nanoparticles (IPDoc+LL37NPs) compared with free drug in a mouse model of peritoneal carcinomatosis	Nanoparticles and hydrogels	IP Doc+LL37NPs resulted in superior reduction in tumour weight and number of nodules (p < 0.05) compared with free drug delivery	IP Doc+LL37NPs led to a significant prolongation of survival in tumour-bearing mice compared with free drug (p < 0.001)
Zhang et al., 2015, China [66]	10	Mouse model	To develop a gel-forming drug delivery system for peritoneal carcinomatosis	Micelles and hydrogels	In vitro: micelle-associated drug delivery demonstrated higher cytotoxicity and apoptotic induction In vivo: hydrogel-associated drug delivery resulted in reduced tumour proliferative activity, increased tumour cell apoptosis, and reduced tumour angiogenesis
Xu et al., 2016, China [64]	8	Mouse model	To develop a hydrogel nanoparticle—paclitaxel (PTX/PECT) formulation for enhanced IP chemotherapeutic effectiveness in a mouse model of CPM	Nanoparticles Hydrogels	PTX/PECT gel decreased tumour weight vs. control (p < 0.01) and vs. free drug (p < 0.05)			Half-life of PXT/PECT gel was found to be 17-fold greater than free drug (p < 0.001)
Yun et al., 2017, China [65]	72	Mouse model	To develop and test a novel hydrogel drug delivery system through the combination of 5-FU loaded polymeric micelles and cisplatin in biodegradable thermosensitive chitosan hydrogel	Micelles and hydrogels	Use of the chitosan hydrogel as a carrier for cisplatin resulted in a significant reduction in the number and weight of tumour nodules (p < 0.05)	Survival CS hydrogel (43 days) Free drug (36 days) (p < 0.05)
Pascale et al., 2017, France [57]	12	Rabbit model	To assess the technical feasibility and oncological efficacy of laparoscopic subperitoneal injection of doxorubicin-loaded microspheres for treatment of CPM in a rabbit model Effect of controlled-release chemotherapy on the growth and viability of CPM rabbits	Microspheres	At 7 days following treatment CPM tumour volume was found to be significantly lower in the doxorubicin-loaded microspheres group compared with control (p = 0.0425)	Proportion of viable tumour at 7 days posttreatment Doxorubicin microspheres group 38% Control group 56% (p = 0.0202)

HA: hyaluronic acid; micro-SPECT/CT: micro single-photon emission computed tomography.